Submissions for variant NM_000038.6(APC):c.6245A>G (p.Asp2082Gly)

gnomAD frequency: 0.00001  dbSNP: rs554370603

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565808	SCV000667348	likely benign	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000565808	SCV000681790	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2082 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 3/250622 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003476334	SCV000768183	uncertain significance	Familial adenomatous polyposis 1	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2082 of the APC protein (p.Asp2082Gly). This variant is present in population databases (rs554370603, gnomAD 0.006%). 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: 482252). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
PreventionGenetics, part of Exact Sciences	RCV000679077	SCV000805449	uncertain significance	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679077	SCV000888758	uncertain significance	not provided	2017-09-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000679077	SCV002765563	uncertain significance	not provided	2022-12-14	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28002797)
Baylor Genetics	RCV003476334	SCV004202193	uncertain significance	Familial adenomatous polyposis 1	2023-08-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000942	SCV004840332	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2082 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 3/250622 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.