ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2476T>G (p.Leu826Val)

gnomAD frequency: 0.00054  dbSNP: rs145245264
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130791 SCV000185685 likely benign Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV002228498 SCV000254001 likely benign Familial adenomatous polyposis 1 2021-12-18 criteria provided, single submitter clinical testing
GeneDx RCV001711298 SCV000564566 likely benign not provided 2021-06-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26580448, 25186627)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000199213 SCV000891078 likely benign Familial adenomatous polyposis 1 2021-08-05 criteria provided, single submitter clinical testing The APC c.2476T>G (p.Leu826Val) missense change has a maximum subpopulation frequency of 0.16% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112173767-T-G). This is higher than the reported incidence of APC-related familial adenomatous polyposis (BS1). Several in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two females of African ancestry with breast cancer (PMID: 25186627). To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4.
Color Diagnostics, LLC DBA Color Health RCV000130791 SCV000911205 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000482678 SCV000916506 likely benign not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: APC c.2476T>G (p.Leu826Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250976 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2476T>G has been reported in the literature in individuals affected with breast cancer and pediatric cancer (Tung_2014, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000482678 SCV002068615 benign not specified 2021-04-29 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130791 SCV002531742 likely benign Hereditary cancer-predisposing syndrome 2020-12-03 criteria provided, single submitter curation

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