Submissions for variant NM_000038.6(APC):c.6785G>T (p.Ser2262Ile)

gnomAD frequency: 0.00001  dbSNP: rs878853465

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563256	SCV000282804	uncertain significance	Familial adenomatous polyposis 1	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2262 of the APC protein (p.Ser2262Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 236635). 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.
Color Diagnostics, LLC DBA Color Health	RCV000581040	SCV000681826	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 2262 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 hereditary cancer in the literature. This variant has been identified in 1/251024 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	RCV000581040	SCV002534507	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Ambry Genetics	RCV000581040	SCV002666244	likely benign	Hereditary cancer-predisposing syndrome	2024-07-16	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.
All of Us Research Program, National Institutes of Health	RCV003998684	SCV004843464	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 2262 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 hereditary cancer in the literature. This variant has been identified in 1/251024 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.
CeGaT Center for Human Genetics Tuebingen	RCV004546461	SCV005042525	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	APC: PM2, BP1, BP4