Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000199213 | SCV003836593 | benign | Familial adenomatous polyposis 1 | 2023-02-25 | reviewed by expert panel | curation | The c.2476T>G variant in APC is a missense variant predicted to cause a substitution of leucine by valine at amino acid position 826 (p.Leu826Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1576% in the non-cancer African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). Additionally, APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel as a gene for which primarily truncating variants are known to cause disease (BP1). Multiple lines of computational evidence suggest no splicing impact. In summary, this variant meets the criteria to be classified as Benign for FAP. ACMG/AMP criteria applied, as specified by the ClinGen/InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel: BA1, BP1 (VCEP specifications version 1; date of approval: 12/12/2022). |
Ambry Genetics | RCV000130791 | SCV000185685 | likely benign | Hereditary cancer-predisposing syndrome | 2018-08-29 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Invitae | RCV003534382 | SCV000254001 | likely benign | Familial adenomatous polyposis 1 | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Gene |
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. |
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, |
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, |
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, |
RCV000482678 | SCV002068615 | benign | not specified | 2021-04-29 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000130791 | SCV002531742 | likely benign | Hereditary cancer-predisposing syndrome | 2020-12-03 | criteria provided, single submitter | curation | |
Fulgent Genetics, |
RCV002492506 | SCV002797397 | likely benign | Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach | 2021-08-04 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001711298 | SCV004222080 | benign | not provided | 2022-12-19 | criteria provided, single submitter | clinical testing |