Submissions for variant NM_000038.6(APC):c.1441G>A (p.Val481Met)

gnomAD frequency: 0.00001  dbSNP: rs587780542

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119171	SCV000153901	uncertain significance	Familial adenomatous polyposis 1	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 481 of the APC protein (p.Val481Met). This variant is present in population databases (rs587780542, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 132722). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000164862	SCV000215546	benign	Hereditary cancer-predisposing syndrome	2024-08-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000585957	SCV000564565	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal or family history of breast, ovarian, or colon cancer (Zidan et al., 2017); This variant is associated with the following publications: (PMID: 18199528, 28828701)
Color Diagnostics, LLC DBA Color Health	RCV000164862	SCV000681461	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 481 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/282556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469015	SCV000693997	uncertain significance	not specified	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: APC c.1441G>A (p.Val481Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1441G>A has been reported in the literature in one individual affected with Breast or Ovarian cancer (Zadin_2017) without strong evidence for causality. This report does 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000119171	SCV000785008	uncertain significance	Familial adenomatous polyposis 1	2017-03-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585957	SCV001133299	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000119171	SCV001136884	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164862	SCV002535563	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000119171	SCV004018811	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000119171	SCV004196455	uncertain significance	Familial adenomatous polyposis 1	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997301	SCV004837402	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 481 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.