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Copy pathClinVarVariationRelease_p53Example.xml
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ClinVarVariationRelease_p53Example.xml
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<?xml version="1.0" encoding="UTF-8" standalone="yes"?>
<ClinVarVariationRelease xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:noNamespaceSchemaLocation="http://ftp.ncbi.nlm.nih.gov/pub/clinvar/xsd_public/clinvar_variation/variation_archive_1.10.xsd" ReleaseDate="2021-01-02">
<VariationArchive VariationID="428898" VariationName="NM_001126112.2(TP53):c.993+1del" VariationType="Deletion" DateCreated="2017-06-29" DateLastUpdated="2021-01-02" Accession="VCV000428898" Version="5" RecordType="interpreted" NumberOfSubmissions="3" NumberOfSubmitters="3">
<RecordStatus>current</RecordStatus>
<Species>Homo sapiens</Species>
<InterpretedRecord>
<SimpleAllele AlleleID="420638" VariationID="428898">
<GeneList>
<Gene Symbol="TP53" FullName="tumor protein p53" GeneID="7157" HGNC_ID="HGNC:11998" Source="submitted" RelationshipType="within single gene">
<Location>
<CytogeneticLocation>17p13.1</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" AssemblyStatus="current" Chr="17" Accession="NC_000017.11" start="7668421" stop="7687490" display_start="7668421" display_stop="7687490" Strand="-"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="17" Accession="NC_000017.10" start="7571719" stop="7590867" display_start="7571719" display_stop="7590867" Strand="-"/>
</Location>
<OMIM>191170</OMIM>
<Haploinsufficiency last_evaluated="2016-09-08" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=TP53">Sufficient evidence for dosage pathogenicity</Haploinsufficiency>
<Triplosensitivity last_evaluated="2016-09-08" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=TP53">No evidence available</Triplosensitivity>
<Property>gene_acmg_incidental_2013</Property>
<Property>gene_acmg_incidental_2016</Property>
</Gene>
</GeneList>
<Name>NM_001126112.2(TP53):c.993+1del</Name>
<CanonicalSPDI>NC_000017.11:7673533:CC:C</CanonicalSPDI>
<VariantType>Deletion</VariantType>
<Location>
<CytogeneticLocation>17p13.1</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" forDisplay="true" AssemblyStatus="current" Chr="17" Accession="NC_000017.11" start="7673534" stop="7673534" display_start="7673534" display_stop="7673534" variantLength="1" positionVCF="7673533" referenceAlleleVCF="AC" alternateAlleleVCF="A"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="17" Accession="NC_000017.10" start="7576852" stop="7576852" display_start="7576852" display_stop="7576852" variantLength="1" positionVCF="7576851" referenceAlleleVCF="AC" alternateAlleleVCF="A"/>
</Location>
<HGVSlist>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t5" sequenceAccession="LRG_321t5">
<Expression>LRG_321t5:c.597+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t6" sequenceAccession="LRG_321t6">
<Expression>LRG_321t6:c.597+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t7" sequenceAccession="LRG_321t7">
<Expression>LRG_321t7:c.597+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t8" sequenceAccession="LRG_321t8">
<Expression>LRG_321t8:c.876+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t1" sequenceAccession="LRG_321t1">
<Expression>LRG_321t1:c.993+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t2" sequenceAccession="LRG_321t2">
<Expression>LRG_321t2:c.993+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Assembly="GRCh37" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000017.10" sequenceAccession="NC_000017" sequenceVersion="10" change="g.7576853del" Assembly="GRCh37">
<Expression>NC_000017.10:g.7576853del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Assembly="GRCh38" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000017.11" sequenceAccession="NC_000017" sequenceVersion="11" change="g.7673535del" Assembly="GRCh38">
<Expression>NC_000017.11:g.7673535del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126112.2" sequenceAccession="NM_001126112" sequenceVersion="2" change="c.993+1del">
<Expression>NM_001126112.2:c.993+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_000546.5" sequenceAccession="NM_000546" sequenceVersion="5" change="c.993+1del">
<Expression>NM_000546.5:c.993+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126113.2" sequenceAccession="NM_001126113" sequenceVersion="2" change="c.993+1del">
<Expression>NM_001126113.2:c.993+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126114.2" sequenceAccession="NM_001126114" sequenceVersion="2" change="c.993+1del">
<Expression>NM_001126114.2:c.993+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126118.1" sequenceAccession="NM_001126118" sequenceVersion="1" change="c.876+1del">
<Expression>NM_001126118.1:c.876+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276761.2" sequenceAccession="NM_001276761" sequenceVersion="2" change="c.876+1del">
<Expression>NM_001276761.2:c.876+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276760.2" sequenceAccession="NM_001276760" sequenceVersion="2" change="c.876+1del">
<Expression>NM_001276760.2:c.876+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276695.2" sequenceAccession="NM_001276695" sequenceVersion="2" change="c.876+1del">
<Expression>NM_001276695.2:c.876+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276696.2" sequenceAccession="NM_001276696" sequenceVersion="2" change="c.876+1del">
<Expression>NM_001276696.2:c.876+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126115.1" sequenceAccession="NM_001126115" sequenceVersion="1" change="c.597+1del">
<Expression>NM_001126115.1:c.597+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126117.1" sequenceAccession="NM_001126117" sequenceVersion="1" change="c.597+1del">
<Expression>NM_001126117.1:c.597+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001126116.1" sequenceAccession="NM_001126116" sequenceVersion="1" change="c.597+1del">
<Expression>NM_001126116.1:c.597+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276697.2" sequenceAccession="NM_001276697" sequenceVersion="2" change="c.516+1del">
<Expression>NM_001276697.2:c.516+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276699.2" sequenceAccession="NM_001276699" sequenceVersion="2" change="c.516+1del">
<Expression>NM_001276699.2:c.516+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001276698.2" sequenceAccession="NM_001276698" sequenceVersion="2" change="c.516+1del">
<Expression>NM_001276698.2:c.516+1del</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001575" Type="splice donor variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t4" sequenceAccession="LRG_321t4">
<Expression>LRG_321t4:c.993+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_321t3" sequenceAccession="LRG_321t3">
<Expression>LRG_321t3:c.993+1del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_000546.5" sequenceAccession="NM_000546" sequenceVersion="5" change="c.993+1delG">
<Expression>NM_000546.5(TP53):c.993+1delG</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_000546.5" sequenceAccession="NM_000546" sequenceVersion="5" change="c.993+1delG">
<Expression>NM_000546.5:c.993+1delG</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="LRG_321" sequenceAccession="LRG_321">
<Expression>LRG_321:g.19017del</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="NG_017013.2" sequenceAccession="NG_017013" sequenceVersion="2" change="g.19017del">
<Expression>NG_017013.2:g.19017del</Expression>
</NucleotideExpression>
</HGVS>
</HGVSlist>
<XRefList>
<XRef ID="CA645369685" DB="ClinGen"/>
<XRef Type="rs" ID="1131691033" DB="dbSNP"/>
</XRefList>
</SimpleAllele>
<ReviewStatus>reviewed by expert panel</ReviewStatus>
<RCVList>
<RCVAccession Title="NM_001126112.2(TP53):c.993+1del AND Hereditary cancer-predisposing syndrome" DateLastEvaluated="2014-04-25" ReviewStatus="criteria provided, single submitter" Interpretation="Pathogenic" SubmissionCount="1" Accession="RCV000492434" Version="1">
<InterpretedConditionList TraitSetID="13598">
<InterpretedCondition DB="MedGen" ID="C0027672">Hereditary cancer-predisposing syndrome</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
<RCVAccession Title="NM_001126112.2(TP53):c.993+1del AND Li-Fraumeni syndrome" DateLastEvaluated="2019-08-28" ReviewStatus="reviewed by expert panel" Interpretation="Pathogenic" SubmissionCount="2" Accession="RCV000991147" Version="2">
<InterpretedConditionList TraitSetID="2589">
<InterpretedCondition DB="MedGen" ID="C0085390">Li-Fraumeni syndrome</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
</RCVList>
<Interpretations>
<Interpretation DateLastEvaluated="2019-08-28" NumberOfSubmissions="3" NumberOfSubmitters="3" Type="Clinical significance">
<Description>Pathogenic</Description>
<Citation Type="general">
<ID Source="PubMed">10980596</ID>
</Citation>
<Citation Type="general">
<URL>https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a608c703-2232-4c79-86dd-00844776434d</URL>
</Citation>
<ConditionList>
<TraitSet ID="13598" Type="Disease">
<Trait ID="18746" Type="Disease">
<Name>
<ElementValue Type="Alternate">Neoplastic Syndromes, Hereditary</ElementValue>
<XRef ID="D009386" DB="MeSH"/>
</Name>
<Name>
<ElementValue Type="Preferred">Hereditary cancer-predisposing syndrome</ElementValue>
<XRef ID="699346009" DB="SNOMED CT"/>
</Name>
<Name>
<ElementValue Type="Alternate">Tumor predisposition</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">Cancer predisposition</ElementValue>
<XRef ID="Hereditary+Cancer/3345" DB="Genetic Alliance"/>
</Name>
<AttributeSet>
<Attribute Type="keyword">Neoplasm</Attribute>
</AttributeSet>
<AttributeSet>
<Attribute Type="keyword">Hereditary cancer syndrome</Attribute>
</AttributeSet>
<Citation Type="practice guideline" Abbrev="IARC, 2008">
<ID Source="pmc">3075918</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="ACMG/NSGC, 2015">
<ID Source="PubMed">25394175</ID>
</Citation>
<XRef ID="140162" DB="Orphanet"/>
<XRef ID="C0027672" DB="MedGen"/>
<XRef ID="MONDO:0015356" DB="MONDO"/>
</Trait>
</TraitSet>
<TraitSet ID="2589" Type="Disease">
<Trait ID="10539" Type="Disease">
<Name>
<ElementValue Type="Preferred">Li-Fraumeni syndrome</ElementValue>
<XRef ID="li-fraumeni-syndrome" DB="Genetics Home Reference"/>
<XRef Type="Phenotypic series" ID="PS151623" DB="OMIM"/>
<XRef ID="428850001" DB="SNOMED CT"/>
</Name>
<Name>
<ElementValue Type="Alternate">Sarcoma family syndrome of Li and Fraumeni</ElementValue>
</Name>
<Symbol>
<ElementValue Type="Preferred">LFS</ElementValue>
</Symbol>
<AttributeSet>
<Attribute Type="GARD id" integerValue="6902"/>
<XRef ID="6902" DB="Office of Rare Diseases"/>
</AttributeSet>
<AttributeSet>
<Attribute Type="public definition">Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies. The lifetime risk of cancer in individuals with LFS is =70% for men and =90% for women. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. LFS is associated with an increased risk of several additional cancers including leukemia, lymphoma, gastrointestinal cancers, cancers of head and neck, kidney, larynx, lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid. Individuals with LFS are at increased risk for cancer in childhood and young adulthood; survivors are at increased risk for multiple primary cancers.</Attribute>
<XRef ID="NBK1311" DB="GeneReviews"/>
</AttributeSet>
<Citation Type="review" Abbrev="GeneReviews">
<ID Source="PubMed">20301488</ID>
<ID Source="BookShelf">NBK1311</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="ACS, 2007">
<ID Source="PubMed">17392385</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="ASCO, 2014">
<ID Source="PubMed">24493721</ID>
</Citation>
<XRef ID="524" DB="Orphanet"/>
<XRef ID="C0085390" DB="MedGen"/>
<XRef ID="MONDO:0018875" DB="MONDO"/>
<XRef Type="Phenotypic series" ID="PS151623" DB="OMIM"/>
</Trait>
</TraitSet>
</ConditionList>
</Interpretation>
</Interpretations>
<ClinicalAssertionList>
<ClinicalAssertion FDARecognizedDatabase="true" ID="2253716" DateCreated="2020-01-10" DateLastUpdated="2020-07-22" SubmissionDate="2019-09-23">
<ClinVarSubmissionID localKey="a608c703-2232-4c79-86dd-00844776434d" localKeyIsSubmitted="1" submittedAssembly="GRCh38"/>
<ClinVarAccession Accession="SCV001142556" Type="SCV" Version="1" SubmitterName="ClinGen TP53 Variant Curation Expert Panel,ClinGen" OrgID="507142" OrganizationCategory="consortium"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>reviewed by expert panel</ReviewStatus>
<Interpretation DateLastEvaluated="2019-08-28">
<Description>Pathogenic</Description>
<Citation>
<ID Source="PubMed">10980596</ID>
</Citation>
<Citation>
<URL>https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a608c703-2232-4c79-86dd-00844776434d</URL>
</Citation>
<Comment>The c.993+1delG variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in a proband meeting classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 10980596). This variant was found to co-segregation with disease in multiple affected family members, with 5 meioses observed (PP1_Moderate; PMID: 10980596). In summary, TP53 c.993+1delG meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting, PP1_Moderate.</Comment>
</Interpretation>
<Assertion>variation to disease</Assertion>
<AttributeSet>
<Attribute Type="ModeOfInheritance">Autosomal dominant inheritance</Attribute>
</AttributeSet>
<AttributeSet>
<Attribute Type="AssertionMethod">ClinGen TP53 ACMG Specifications v1</Attribute>
<Citation>
<URL>https://submit.ncbi.nlm.nih.gov/ft/byid/n2mxzzq1/clingen_tp53_acmg_specifications_v1.pdf</URL>
</Citation>
</AttributeSet>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
</Sample>
<Method>
<MethodType>curation</MethodType>
</Method>
<ObservedData>
<Attribute Type="Description">not provided</Attribute>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<GeneList>
<Gene Symbol="TP53"/>
</GeneList>
<VariantType>Variation</VariantType>
<OtherNameList>
<Name>NM_000546.5(TP53):c.993+1delG</Name>
</OtherNameList>
<AttributeSet>
<Attribute Type="HGVS">NC_000017.11:g.7673534delC</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<XRef DB="Orphanet" ID="ORPHA524"/>
</Trait>
</TraitSet>
<SubmissionNameList>
<SubmissionName>SUB6336842</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
<ClinicalAssertion ID="2702937" DateCreated="2020-07-06" DateLastUpdated="2020-07-11" SubmissionDate="2020-07-01">
<ClinVarSubmissionID localKey="NM_000546.5:c.993+1delG|MedGen:C0085390" submittedAssembly="GRCh37"/>
<ClinVarAccession Accession="SCV001370554" Type="SCV" Version="1" SubmitterName="Integrated Genetics/Laboratory Corporation of America" OrgID="500026" OrganizationCategory="laboratory" OrgAbbreviation="IG"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>criteria provided, single submitter</ReviewStatus>
<Interpretation DateLastEvaluated="2020-05-05">
<Description>Pathogenic</Description>
<Citation>
<ID Source="PubMed">10980596</ID>
</Citation>
<Comment>Variant summary: TP53 c.993+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. These predictions were confirmed by a publication that demonstrated exon 9 skipping in a patient derived immortalized cell line, and the lack of the variant-transcript in mRNA isolated from patient derived leukocytes (Verselis_2000). The variant was absent in 251342 control chromosomes (gnomAD). c.993+1delG has been reported in the literature in a large family, in multiple family members affected with various tumors belonging to the Li-Fraumeni Syndrome tumor spectrum (Verselis_2000); this family met the classic Li-Fraumeni syndrome criteria, and the variant co-segregated with the disease in multiple family members. These data indicate that the variant is likely to be associated with disease. One submitter (i.e. ClinGen TP53 Variant Curation Expert Panel) has provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.</Comment>
</Interpretation>
<Assertion>variation to disease</Assertion>
<AttributeSet>
<Attribute Type="AssertionMethod">LabCorp Variant Classification Summary - May 2015</Attribute>
<Citation>
<URL>https://submit.ncbi.nlm.nih.gov/ft/byid/pttb9itm/labcorp_variant_classification_method_-_may_2015.pdf</URL>
</Citation>
</AttributeSet>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
</Sample>
<Method>
<MethodType>clinical testing</MethodType>
</Method>
<ObservedData>
<Attribute Type="Description">not provided</Attribute>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<GeneList>
<Gene Symbol="TP53"/>
</GeneList>
<VariantType>Variation</VariantType>
<AttributeSet>
<Attribute Type="HGVS">NM_000546.5:c.993+1delG</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<Name>
<ElementValue Type="Preferred">Li-Fraumeni syndrome</ElementValue>
</Name>
<XRef DB="MedGen" ID="C0085390" Type="CUI"/>
</Trait>
</TraitSet>
<SubmissionNameList>
<SubmissionName>SUB7703337</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
<ClinicalAssertion ID="1132179" DateCreated="2017-06-29" DateLastUpdated="2020-12-08" SubmissionDate="2020-11-30">
<ClinVarSubmissionID localKey="a97612" localKeyIsSubmitted="1" submittedAssembly="GRCh37"/>
<ClinVarAccession Accession="SCV000581155" Type="SCV" Version="4" SubmitterName="Ambry Genetics" OrgID="61756" OrganizationCategory="laboratory"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>criteria provided, single submitter</ReviewStatus>
<Interpretation DateLastEvaluated="2014-04-25">
<Description>Pathogenic</Description>
<Comment>​The c.993+1delG intronic pathogenic mutation results from a deletion of the first nucleotide after coding exon 8 of the TP53 gene. This mutation tracked with disease in a large family with multiple members diagnosed with a wide spectrum of Li-Fraumeni related cancers. RT-PCR analyses showed that this alteration, referred to as IVS9+1delG, led to exon 9 skipping (Verselis SJ et al. Oncogene. 2000 Aug 31;19(37):4230-5). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).</Comment>
</Interpretation>
<Assertion>variation to disease</Assertion>
<AttributeSet>
<Attribute Type="AssertionMethod">Ambry Autosomal Dominant and X-Linked criteria (10/2015)</Attribute>
<Citation>
<URL>https://submit.ncbi.nlm.nih.gov/ft/byid/aH4uL7vL/mid-7377_ambry_classification_scheme_oct_2015.pdf</URL>
</Citation>
</AttributeSet>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
<NumberTested>1</NumberTested>
</Sample>
<Method>
<MethodType>clinical testing</MethodType>
</Method>
<ObservedData>
<Attribute Type="VariantAlleles" integerValue="1"/>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<GeneList>
<Gene Symbol="TP53"/>
</GeneList>
<VariantType>Variation</VariantType>
<AttributeSet>
<Attribute Type="HGVS">NM_000546.4:c.993+1delG</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<Name>
<ElementValue Type="Preferred">Hereditary cancer-predisposing syndrome</ElementValue>
</Name>
<XRef DB="MedGen" ID="C0027672" Type="CUI"/>
</Trait>
</TraitSet>
<SubmissionNameList>
<SubmissionName>NonExomeUpdate_081220AmbryReport</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
</ClinicalAssertionList>
<TraitMappingList>
<TraitMapping ClinicalAssertionID="2702937" TraitType="Disease" MappingType="Name" MappingValue="Li-Fraumeni syndrome" MappingRef="Preferred">
<MedGen CUI="C0085390" Name="Li-Fraumeni syndrome"/>
</TraitMapping>
<TraitMapping ClinicalAssertionID="1132179" TraitType="Disease" MappingType="Name" MappingValue="Hereditary cancer-predisposing syndrome" MappingRef="Preferred">
<MedGen CUI="C0027672" Name="Hereditary cancer-predisposing syndrome"/>
</TraitMapping>
<TraitMapping ClinicalAssertionID="2253716" TraitType="Disease" MappingType="XRef" MappingValue="ORPHA524" MappingRef="Orphanet">
<MedGen CUI="C0085390" Name="Li-Fraumeni syndrome"/>
</TraitMapping>
</TraitMappingList>
</InterpretedRecord>
</VariationArchive>
<VariationArchive VariationID="429070" VariationName="NM_000051.3(ATM):c.2639-384A>G" VariationType="single nucleotide variant" DateCreated="2017-06-30" DateLastUpdated="2021-01-02" Accession="VCV000429070" Version="5" RecordType="interpreted" NumberOfSubmissions="3" NumberOfSubmitters="3">
<RecordStatus>current</RecordStatus>
<Species>Homo sapiens</Species>
<InterpretedRecord>
<SimpleAllele AlleleID="421073" VariationID="429070">
<GeneList>
<Gene Symbol="ATM" FullName="ATM serine/threonine kinase" GeneID="472" HGNC_ID="HGNC:795" Source="submitted" RelationshipType="within single gene">
<Location>
<CytogeneticLocation>11q22.3</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" AssemblyStatus="current" Chr="11" Accession="NC_000011.10" start="108222484" stop="108369102" display_start="108222484" display_stop="108369102" Strand="+"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="11" Accession="NC_000011.9" start="108093558" stop="108239825" display_start="108093558" display_stop="108239825" Strand="+"/>
</Location>
<OMIM>607585</OMIM>
<Haploinsufficiency last_evaluated="2020-04-08" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=ATM">Sufficient evidence for dosage pathogenicity</Haploinsufficiency>
<Triplosensitivity last_evaluated="2020-04-08" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=ATM">No evidence available</Triplosensitivity>
</Gene>
</GeneList>
<Name>NM_000051.3(ATM):c.2639-384A>G</Name>
<CanonicalSPDI>NC_000011.10:108268025:A:G</CanonicalSPDI>
<VariantType>single nucleotide variant</VariantType>
<Location>
<CytogeneticLocation>11q22.3</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" forDisplay="true" AssemblyStatus="current" Chr="11" Accession="NC_000011.10" start="108268026" stop="108268026" display_start="108268026" display_stop="108268026" variantLength="1" positionVCF="108268026" referenceAlleleVCF="A" alternateAlleleVCF="G"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="11" Accession="NC_000011.9" start="108138753" stop="108138753" display_start="108138753" display_stop="108138753" variantLength="1" positionVCF="108138753" referenceAlleleVCF="A" alternateAlleleVCF="G"/>
</Location>
<HGVSlist>
<HGVS Assembly="GRCh38" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000011.10" sequenceAccession="NC_000011" sequenceVersion="10" change="g.108268026A>G" Assembly="GRCh38">
<Expression>NC_000011.10:g.108268026A>G</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Assembly="GRCh37" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000011.9" sequenceAccession="NC_000011" sequenceVersion="9" change="g.108138753A>G" Assembly="GRCh37">
<Expression>NC_000011.9:g.108138753A>G</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_001351834.2" sequenceAccession="NM_001351834" sequenceVersion="2" change="c.2639-384A>G">
<Expression>NM_001351834.2:c.2639-384A>G</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001627" Type="intron variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_000051.3" sequenceAccession="NM_000051" sequenceVersion="3" change="c.2639-384A>G">
<Expression>NM_000051.3:c.2639-384A>G</Expression>
</NucleotideExpression>
<MolecularConsequence ID="SO:0001627" Type="intron variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_135t1" sequenceAccession="LRG_135t1" change="c.2639-384A>G">
<Expression>LRG_135t1:c.2639-384A>G</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="NG_009830.1" sequenceAccession="NG_009830" sequenceVersion="1" change="g.50195A>G">
<Expression>NG_009830.1:g.50195A>G</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="LRG_135" sequenceAccession="LRG_135" change="g.50195A>G">
<Expression>LRG_135:g.50195A>G</Expression>
</NucleotideExpression>
</HGVS>
</HGVSlist>
<XRefList>
<XRef ID="CA601698081" DB="ClinGen"/>
<XRef Type="rs" ID="1131691154" DB="dbSNP"/>
</XRefList>
<AlleleFrequencyList>
<AlleleFrequency Value="0.00002" Source="Trans-Omics for Precision Medicine (TOPMed)"/>
<AlleleFrequency Value="0.00003" Source="The Genome Aggregation Database (gnomAD)"/>
</AlleleFrequencyList>
</SimpleAllele>
<ReviewStatus>criteria provided, multiple submitters, no conflicts</ReviewStatus>
<RCVList>
<RCVAccession Title="NM_000051.3(ATM):c.2639-384A>G AND Hereditary cancer-predisposing syndrome" DateLastEvaluated="2020-07-14" ReviewStatus="criteria provided, multiple submitters, no conflicts" Interpretation="Likely pathogenic" SubmissionCount="2" Accession="RCV000493875" Version="3">
<InterpretedConditionList TraitSetID="13598">
<InterpretedCondition DB="MedGen" ID="C0027672">Hereditary cancer-predisposing syndrome</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
<RCVAccession Title="NM_000051.3(ATM):c.2639-384A>G AND Ataxia-telangiectasia syndrome" DateLastEvaluated="2020-09-16" ReviewStatus="no assertion criteria provided" Interpretation="Likely pathogenic" SubmissionCount="1" Accession="RCV001271168" Version="1">
<InterpretedConditionList TraitSetID="770">
<InterpretedCondition DB="MedGen" ID="C0004135">Ataxia-telangiectasia syndrome</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
</RCVList>
<Interpretations>
<Interpretation DateLastEvaluated="2020-07-14" NumberOfSubmissions="3" NumberOfSubmitters="3" Type="Clinical significance">
<Description>Likely pathogenic</Description>
<Citation Type="general">
<ID Source="PubMed">22006793</ID>
</Citation>
<Citation Type="general">
<ID Source="PubMed">24506781</ID>
</Citation>
<Citation Type="general">
<ID Source="PubMed">31050087</ID>
</Citation>
<ConditionList>
<TraitSet ID="13598" Type="Disease">
<Trait ID="18746" Type="Disease">
<Name>
<ElementValue Type="Alternate">Neoplastic Syndromes, Hereditary</ElementValue>
<XRef ID="D009386" DB="MeSH"/>
</Name>
<Name>
<ElementValue Type="Preferred">Hereditary cancer-predisposing syndrome</ElementValue>
<XRef ID="699346009" DB="SNOMED CT"/>
</Name>
<Name>
<ElementValue Type="Alternate">Tumor predisposition</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">Cancer predisposition</ElementValue>
<XRef ID="Hereditary+Cancer/3345" DB="Genetic Alliance"/>
</Name>
<AttributeSet>
<Attribute Type="keyword">Neoplasm</Attribute>
</AttributeSet>
<AttributeSet>
<Attribute Type="keyword">Hereditary cancer syndrome</Attribute>
</AttributeSet>
<Citation Type="practice guideline" Abbrev="IARC, 2008">
<ID Source="pmc">3075918</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="ACMG/NSGC, 2015">
<ID Source="PubMed">25394175</ID>
</Citation>
<XRef ID="140162" DB="Orphanet"/>
<XRef ID="C0027672" DB="MedGen"/>
<XRef ID="MONDO:0015356" DB="MONDO"/>
</Trait>
</TraitSet>
<TraitSet ID="770" Type="Disease">
<Trait ID="4635" Type="Disease">
<Name>
<ElementValue Type="Alternate">Louis-Bar syndrome</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">Cerebello-oculocutaneous telangiectasia</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">Immunodeficiency with ataxia telangiectasia</ElementValue>
</Name>
<Name>
<ElementValue Type="Preferred">Ataxia-telangiectasia syndrome</ElementValue>
<XRef ID="Ataxia+Telangiectasia/637" DB="Genetic Alliance"/>
<XRef ID="68504005" DB="SNOMED CT"/>
</Name>
<Name>
<ElementValue Type="Alternate">Ataxia-telangiectasia, complementation group D</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">AT, COMPLEMENTATION GROUP C</ElementValue>
<XRef ID="208900" DB="OMIM"/>
</Name>
<Name>
<ElementValue Type="Alternate">ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP A</ElementValue>
<XRef Type="Allelic variant" ID="607585.0001" DB="OMIM"/>
</Name>
<Name>
<ElementValue Type="Alternate">ATAXIA-TELANGIECTASIA, FRESNO VARIANT</ElementValue>
<XRef Type="Allelic variant" ID="607585.0014" DB="OMIM"/>
</Name>
<Name>
<ElementValue Type="Alternate">Ataxia-telangiectasia</ElementValue>
</Name>
<Name>
<ElementValue Type="Alternate">Ataxia-telangiectasia, complementation group E</ElementValue>
</Name>
<Symbol>
<ElementValue Type="Alternate">AT1</ElementValue>
<XRef Type="MIM" ID="208900" DB="OMIM"/>
</Symbol>
<Symbol>
<ElementValue Type="Preferred">AT</ElementValue>
<XRef Type="MIM" ID="208900" DB="OMIM"/>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">A-T</ElementValue>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">ATM</ElementValue>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">ATC</ElementValue>
<XRef ID="208900" DB="OMIM"/>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">ATA</ElementValue>
<XRef ID="208900" DB="OMIM"/>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">ATD</ElementValue>
<XRef ID="208900" DB="OMIM"/>
</Symbol>
<Symbol>
<ElementValue Type="Alternate">ATE</ElementValue>
<XRef ID="208900" DB="OMIM"/>
</Symbol>
<AttributeSet>
<Attribute Type="keyword">Hereditary cancer syndrome</Attribute>
</AttributeSet>
<AttributeSet>
<Attribute Type="GARD id" integerValue="5862"/>
<XRef ID="5862" DB="Office of Rare Diseases"/>
</AttributeSet>
<Citation Type="review" Abbrev="GeneReviews">
<ID Source="PubMed">20301790</ID>
<ID Source="BookShelf">NBK26468</ID>
</Citation>
<Citation Type="review" Abbrev="GeneReviews">
<ID Source="PubMed">20301317</ID>
<ID Source="BookShelf">NBK1138</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="EFNS, 2010">
<ID Source="PubMed">20050888</ID>
</Citation>
<Citation Type="practice guideline" Abbrev="EFNS/ENS, 2014">
<ID Source="PubMed">24418350</ID>
</Citation>
<XRef ID="100" DB="Orphanet"/>
<XRef ID="C0004135" DB="MedGen"/>
<XRef ID="MONDO:0008840" DB="MONDO"/>
<XRef Type="MIM" ID="208900" DB="OMIM"/>
</Trait>
</TraitSet>
</ConditionList>
</Interpretation>
</Interpretations>
<ClinicalAssertionList>
<ClinicalAssertion ID="2652022" DateCreated="2020-06-19" DateLastUpdated="2020-06-22" SubmissionDate="2020-05-19">
<ClinVarSubmissionID localKey="Db4KrQBSZeoE7-orUyypkZ0ceL479kSI9-BOJSwAJaI|MedGen:C0027672" submittedAssembly="GRCh37"/>
<ClinVarAccession Accession="SCV001343706" Type="SCV" Version="1" SubmitterName="Color" OrgID="505849" OrganizationCategory="laboratory"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>criteria provided, single submitter</ReviewStatus>
<Interpretation DateLastEvaluated="2020-01-09">
<Description>Likely pathogenic</Description>
</Interpretation>
<Assertion>variation to disease</Assertion>
<AttributeSet>
<Attribute Type="AssertionMethod">ACMG Guidelines, 2015</Attribute>
<Citation>
<ID Source="PubMed">25741868</ID>
</Citation>
</AttributeSet>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
</Sample>
<Method>
<TypePlatform>NGS</TypePlatform>
<MethodType>clinical testing</MethodType>
</Method>
<ObservedData>
<Attribute Type="Description">not provided</Attribute>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<GeneList>
<Gene Symbol="ATM"/>
</GeneList>
<VariantType>Variation</VariantType>
<AttributeSet>
<Attribute Type="HGVS">NM_000051.3:c.2639-384A>G</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<Name>
<ElementValue Type="Preferred">Hereditary cancer-predisposing syndrome</ElementValue>
</Name>
<XRef DB="MedGen" ID="C0027672" Type="CUI"/>
</Trait>
</TraitSet>
<Comment>This variant causes an A>G nucleotide substitution at the -384 position of intron 17 of the ATM gene. Functional RNA studies have shown that this variant causes retention of 58 base pairs from intron 17, creating a frameshift and premature translation stop signal (PMID: 22006793, 31050087). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 22006793, 31050087). This variant has also been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.</Comment>
<SubmissionNameList>
<SubmissionName>Color Genomics - ClinVar Submission - May2020 - SUB747</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
<ClinicalAssertion ID="1133201" DateCreated="2017-06-30" DateLastUpdated="2020-12-08" SubmissionDate="2020-11-30">
<ClinVarSubmissionID localKey="a96141" localKeyIsSubmitted="1" submittedAssembly="GRCh37"/>
<ClinVarAccession Accession="SCV000581450" Type="SCV" Version="4" SubmitterName="Ambry Genetics" OrgID="61756" OrganizationCategory="laboratory"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>criteria provided, single submitter</ReviewStatus>
<Interpretation DateLastEvaluated="2020-07-14">
<Description>Likely pathogenic</Description>
<Citation>
<ID Source="PubMed">22006793</ID>
</Citation>
<Citation>
<ID Source="PubMed">24506781</ID>
</Citation>
<Citation>
<ID Source="PubMed">31050087</ID>
</Citation>
<Comment>The c.2639-384A>G intronic variant results from an A to G substitution 384 nucleotides upstream from coding exon 17 in the ATM gene. This alteration has been detected in conjunction with pathogenic ATM variants in individuals affected with ataxia-telangiectasia (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fi&eacute;vet A et al. Hum. Mutat., 2019 10;40:1713-1730). RNA studies have shown that this alteration creates a cryptic splice donor site and leads to the insertion of a 58-bp pseudoexon into the transcript, which is anticipated to result in nonsense mediated RNA decay (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fi&eacute;vet A et al. Hum. Mutat., 2019 10;40:1713-1730, Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.</Comment>
</Interpretation>
<Assertion>variation to disease</Assertion>
<AttributeSet>
<Attribute Type="AssertionMethod">Ambry Autosomal Dominant and X-Linked criteria (2/2020)</Attribute>
<Citation>
<URL>https://submit.ncbi.nlm.nih.gov/ft/byid/izn1iuef/variant_classificationscheme_02.2020_ambry.pdf</URL>
</Citation>
</AttributeSet>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
<NumberTested>1</NumberTested>
</Sample>
<Method>
<MethodType>clinical testing</MethodType>
</Method>
<ObservedData>
<Attribute Type="VariantAlleles" integerValue="1"/>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<GeneList>
<Gene Symbol="ATM"/>
</GeneList>
<VariantType>Variation</VariantType>
<AttributeSet>
<Attribute Type="HGVS">NM_000051.3:c.2639-384A>G</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<Name>
<ElementValue Type="Preferred">Hereditary cancer-predisposing syndrome</ElementValue>
</Name>
<XRef DB="MedGen" ID="C0027672" Type="CUI"/>
</Trait>
</TraitSet>
<SubmissionNameList>
<SubmissionName>NonExomeUpdate_081220AmbryReport</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
<ClinicalAssertion ID="2867319" DateCreated="2020-12-30" DateLastUpdated="2021-01-01" SubmissionDate="2020-12-28">
<ClinVarSubmissionID localKey="NM_000051.3:c.2639-384A>G|Ataxia-telangiectasia" submittedAssembly="GRCh37"/>
<ClinVarAccession Accession="SCV001452044" Type="SCV" Version="1" SubmitterName="Natera, Inc." OrgID="500034" OrganizationCategory="laboratory"/>
<RecordStatus>current</RecordStatus>
<ReviewStatus>no assertion criteria provided</ReviewStatus>
<Interpretation DateLastEvaluated="2020-09-16">
<Description>Likely pathogenic</Description>
</Interpretation>
<Assertion>variation to disease</Assertion>
<ObservedInList>
<ObservedIn>
<Sample>
<Origin>germline</Origin>
<Species TaxonomyId="9606">human</Species>
<AffectedStatus>unknown</AffectedStatus>
</Sample>
<Method>
<MethodType>clinical testing</MethodType>
</Method>
<ObservedData>
<Attribute Type="Description">not provided</Attribute>
</ObservedData>
</ObservedIn>
</ObservedInList>
<SimpleAllele>
<VariantType>Variation</VariantType>
<AttributeSet>
<Attribute Type="HGVS">NM_000051.3:c.2639-384A>G</Attribute>
</AttributeSet>
</SimpleAllele>
<TraitSet Type="Disease">
<Trait Type="Disease">
<Name>
<ElementValue Type="Preferred">Ataxia-telangiectasia</ElementValue>
</Name>
</Trait>
</TraitSet>
<SubmissionNameList>
<SubmissionName>SUB8808661</SubmissionName>
</SubmissionNameList>
</ClinicalAssertion>
</ClinicalAssertionList>
<TraitMappingList>
<TraitMapping ClinicalAssertionID="2867319" TraitType="Disease" MappingType="Name" MappingValue="Ataxia-telangiectasia" MappingRef="Preferred">
<MedGen CUI="C0004135" Name="Ataxia-telangiectasia syndrome"/>
</TraitMapping>
<TraitMapping ClinicalAssertionID="2652022" TraitType="Disease" MappingType="Name" MappingValue="Hereditary cancer-predisposing syndrome" MappingRef="Preferred">
<MedGen CUI="C0027672" Name="Hereditary cancer-predisposing syndrome"/>
</TraitMapping>
<TraitMapping ClinicalAssertionID="1133201" TraitType="Disease" MappingType="Name" MappingValue="Hereditary cancer-predisposing syndrome" MappingRef="Preferred">
<MedGen CUI="C0027672" Name="Hereditary cancer-predisposing syndrome"/>
</TraitMapping>
</TraitMappingList>
</InterpretedRecord>
</VariationArchive>
<VariationArchive VariationID="429171" VariationName="NM_000143.3(FH):c.702T>G (p.Thr234=)" VariationType="single nucleotide variant" DateCreated="2017-06-30" DateLastUpdated="2021-01-02" Accession="VCV000429171" Version="7" RecordType="interpreted" NumberOfSubmissions="4" NumberOfSubmitters="4">
<RecordStatus>current</RecordStatus>
<Species>Homo sapiens</Species>
<InterpretedRecord>
<SimpleAllele AlleleID="421010" VariationID="429171">
<GeneList>
<Gene Symbol="FH" FullName="fumarate hydratase" GeneID="2271" HGNC_ID="HGNC:3700" Source="submitted" RelationshipType="within single gene">
<Location>
<CytogeneticLocation>1q43</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" AssemblyStatus="current" Chr="1" Accession="NC_000001.11" start="241497603" stop="241519755" display_start="241497603" display_stop="241519755" Strand="-"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="1" Accession="NC_000001.10" start="241660856" stop="241683084" display_start="241660856" display_stop="241683084" Strand="-"/>
</Location>
<OMIM>136850</OMIM>
<Haploinsufficiency last_evaluated="2020-07-06" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=FH">Sufficient evidence for dosage pathogenicity</Haploinsufficiency>
<Triplosensitivity last_evaluated="2020-07-06" ClinGen="https://www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/isca_gene.cgi?sym=FH">No evidence available</Triplosensitivity>
</Gene>
</GeneList>
<Name>NM_000143.3(FH):c.702T>G (p.Thr234=)</Name>
<CanonicalSPDI>NC_000001.11:241508638:A:C</CanonicalSPDI>
<VariantType>single nucleotide variant</VariantType>
<Location>
<CytogeneticLocation>1q43</CytogeneticLocation>
<SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38" forDisplay="true" AssemblyStatus="current" Chr="1" Accession="NC_000001.11" start="241508639" stop="241508639" display_start="241508639" display_stop="241508639" variantLength="1" positionVCF="241508639" referenceAlleleVCF="A" alternateAlleleVCF="C"/>
<SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25" AssemblyStatus="previous" Chr="1" Accession="NC_000001.10" start="241671939" stop="241671939" display_start="241671939" display_stop="241671939" variantLength="1" positionVCF="241671939" referenceAlleleVCF="A" alternateAlleleVCF="C"/>
</Location>
<HGVSlist>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="LRG_504" sequenceAccession="LRG_504" change="g.16116T>G">
<Expression>LRG_504:g.16116T>G</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Assembly="GRCh37" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000001.10" sequenceAccession="NC_000001" sequenceVersion="10" change="g.241671939A>C" Assembly="GRCh37">
<Expression>NC_000001.10:g.241671939A>C</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Assembly="GRCh38" Type="genomic, top-level">
<NucleotideExpression sequenceAccessionVersion="NC_000001.11" sequenceAccession="NC_000001" sequenceVersion="11" change="g.241508639A>C" Assembly="GRCh38">
<Expression>NC_000001.11:g.241508639A>C</Expression>
</NucleotideExpression>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="NM_000143.3" sequenceAccession="NM_000143" sequenceVersion="3" change="c.702T>G">
<Expression>NM_000143.3:c.702T>G</Expression>
</NucleotideExpression>
<ProteinExpression sequenceAccessionVersion="NP_000134.2" sequenceAccession="NP_000134" sequenceVersion="2" change="p.Thr234=">
<Expression>NP_000134.2:p.Thr234=</Expression>
</ProteinExpression>
<MolecularConsequence ID="SO:0001819" Type="synonymous variant" DB="SO"/>
</HGVS>
<HGVS Type="coding">
<NucleotideExpression sequenceAccessionVersion="LRG_504t1" sequenceAccession="LRG_504t1" change="c.702T>G">
<Expression>LRG_504t1:c.702T>G</Expression>
</NucleotideExpression>
<ProteinExpression sequenceAccessionVersion="LRG_504p1" sequenceAccession="LRG_504p1" change="p.Thr234=">
<Expression>LRG_504p1:p.Thr234=</Expression>
</ProteinExpression>
</HGVS>
<HGVS Type="genomic">
<NucleotideExpression sequenceAccessionVersion="NG_012338.1" sequenceAccession="NG_012338" sequenceVersion="1" change="g.16116T>G">
<Expression>NG_012338.1:g.16116T>G</Expression>
</NucleotideExpression>
</HGVS>
</HGVSlist>
<XRefList>
<XRef ID="CA1478629" DB="ClinGen"/>
<XRef Type="rs" ID="201083387" DB="dbSNP"/>
</XRefList>
<AlleleFrequencyList>
<AlleleFrequency Value="0.00140" Source="1000 Genomes Project"/>
<AlleleFrequency Value="0.00004" Source="Trans-Omics for Precision Medicine (TOPMed)"/>
<AlleleFrequency Value="0.00048" Source="The Genome Aggregation Database (gnomAD), exomes"/>
<AlleleFrequency Value="0.00054" Source="Exome Aggregation Consortium (ExAC)"/>
</AlleleFrequencyList>
<GlobalMinorAlleleFrequency Value="0.00140" Source="1000 Genomes Project" MinorAllele="C"/>
</SimpleAllele>
<ReviewStatus>criteria provided, multiple submitters, no conflicts</ReviewStatus>
<RCVList>
<RCVAccession Title="NM_000143.3(FH):c.702T>G (p.Thr234=) AND Hereditary cancer-predisposing syndrome" DateLastEvaluated="2019-04-29" ReviewStatus="criteria provided, single submitter" Interpretation="Likely benign" SubmissionCount="1" Accession="RCV000494047" Version="2">
<InterpretedConditionList TraitSetID="13598">
<InterpretedCondition DB="MedGen" ID="C0027672">Hereditary cancer-predisposing syndrome</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
<RCVAccession Title="NM_000143.3(FH):c.702T>G (p.Thr234=) AND not provided" DateLastEvaluated="2018-05-17" ReviewStatus="criteria provided, single submitter" Interpretation="Likely benign" SubmissionCount="1" Accession="RCV000827769" Version="3">
<InterpretedConditionList TraitSetID="9460">
<InterpretedCondition DB="MedGen" ID="CN517202">not provided</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
<RCVAccession Title="NM_000143.3(FH):c.702T>G (p.Thr234=) AND Fumarase deficiency" DateLastEvaluated="2019-12-31" ReviewStatus="criteria provided, single submitter" Interpretation="Benign" SubmissionCount="2" Accession="RCV001083333" Version="2">
<InterpretedConditionList TraitSetID="5266">
<InterpretedCondition DB="MedGen" ID="C0342770">Fumarase deficiency</InterpretedCondition>
</InterpretedConditionList>
</RCVAccession>
</RCVList>
<Interpretations>
<Interpretation DateLastEvaluated="2019-12-31" NumberOfSubmissions="4" NumberOfSubmitters="4" Type="Clinical significance">
<Description>Benign/Likely benign</Description>
<Citation Type="general">
<ID Source="PubMed">19339519</ID>
</Citation>
<DescriptionHistory Dated="2020-03-24">
<Description>Conflicting interpretations of pathogenicity</Description>
</DescriptionHistory>
<DescriptionHistory Dated="2017-12-26">
<Description>Uncertain significance</Description>
</DescriptionHistory>
<ConditionList>
<TraitSet ID="9460" Type="Disease">
<Trait ID="17556" Type="Disease">
<Name>
<ElementValue Type="Preferred">not provided</ElementValue>
<XRef ID="13DG0619" DB="Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre"/>
</Name>
<AttributeSet>
<Attribute Type="public definition">The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.</Attribute>
</AttributeSet>
<XRef ID="CN517202" DB="MedGen"/>
</Trait>
</TraitSet>