Submissions for variant NM_000038.6(APC):c.3242G>A (p.Ser1081Asn)

gnomAD frequency: 0.00001  dbSNP: rs374380039

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204913	SCV000259335	uncertain significance	Familial adenomatous polyposis 1	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1081 of the APC protein (p.Ser1081Asn). This variant is present in population databases (rs374380039, gnomAD 0.01%). 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: 219459). 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	RCV000573936	SCV000667272	likely benign	Hereditary cancer-predisposing syndrome	2023-06-15	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.
Counsyl	RCV000204913	SCV000784972	uncertain significance	Familial adenomatous polyposis 1	2017-02-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573936	SCV000906745	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1081 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 1/31396 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.
Sema4, Sema4	RCV000573936	SCV002533193	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000204913	SCV004019822	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	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	RCV000204913	SCV004206605	uncertain significance	Familial adenomatous polyposis 1	2023-05-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997561	SCV004839785	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1081 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 1/31396 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.
GeneDx	RCV004589876	SCV005079636	uncertain significance	not provided	2024-02-23	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; Identified in an individual with kidney cancer (PMID: 29684080); This variant is associated with the following publications: (PMID: 18199528, 29684080)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004589876	SCV005624222	uncertain significance	not provided	2024-02-20	criteria provided, single submitter	clinical testing	The APC c.3242G>A (p.Ser1081Asn) variant has been reported in the published literature in an individual with melanoma (PMID: 32913981 (2018)). It has also been reported in a renal cell carcinoma sample from The Cancer Genome Atlas (TCGA) dataset (PMID: 29684080 (2018)). The frequency of this variant in the general population, 0.000032 (1/31396 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004739593	SCV005356155	uncertain significance	APC-related disorder	2024-05-05	no assertion criteria provided	clinical testing	The APC c.3242G>A variant is predicted to result in the amino acid substitution p.Ser1081Asn. This variant has been reported with another missense variant in the gene APC in an individual from a cohort study on patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (S9_Table. Yehia et al 2018. PubMed ID: 29684080). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/219459/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.