Submissions for variant NM_000038.6(APC):c.1966C>G (p.Leu656Val)

gnomAD frequency: 0.00003  dbSNP: rs577466163

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568349	SCV000667351	likely benign	Hereditary cancer-predisposing syndrome	2021-06-18	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	RCV003537103	SCV000768097	uncertain significance	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 656 of the APC protein (p.Leu656Val). This variant is present in population databases (rs577466163, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of attenuated adenomatous polyposis (PMID: 31285513). ClinVar contains an entry for this variant (Variation ID: 482253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 (Invitae). 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	RCV000568349	SCV000911506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 656 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 been reported in individuals affected with attenuated familial adenomatous polyposis (PMID: 31285513), breast cancer (DOI: 10.1101/2021.04.15.21255554), or colorectal cancer (PMID: 32635641). This variant has been identified in 7/250602 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.
Mendelics	RCV000646329	SCV001136889	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568349	SCV002534132	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-03	criteria provided, single submitter	curation
Baylor Genetics	RCV000646329	SCV004200076	uncertain significance	Familial adenomatous polyposis 1	2023-09-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478241	SCV004218839	uncertain significance	not provided	2022-11-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (6/34544 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with adenomatous polyposis (PMID: 31285513 (2019)), Lynch-like syndrome (PMID: 32635641 (2020)), and breast cancer (PMID: 35534704 (2022)). 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 damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on APC mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000646329	SCV000844924	uncertain significance	Familial adenomatous polyposis 1	2018-06-01	no assertion criteria provided	clinical testing