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

gnomAD frequency: 0.00003  dbSNP: rs577466163

Total submissions: 11

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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000646329	SCV000768097	uncertain significance	Familial adenomatous polyposis 1	2025-01-14	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). 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.
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	likely benign	Familial adenomatous polyposis 1	2024-04-09	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	2023-12-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478241	SCV004218839	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The APC c.1966C>G (p.Leu656Val) variant has been reported in the published literature in in individuals with adenomatous polyposis (PMID: 31285513 (2019)), Lynch-like syndrome (PMID: 32635641 (2020)), and breast cancer (PMID: 35534704 (2022)). The frequency of this variant in the general population, 0.00017 (6/34544 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004000943	SCV004839631	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-15	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.
GeneDx	RCV003478241	SCV005079035	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32635641, 31285513, 35534704, 18199528)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240218	SCV005887489	uncertain significance	not specified	2025-01-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.1966C>G (p.Leu656Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250602 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1966C>G has been reported in the literature in individuals affected with Attenuated adenomatous polyposis, Lynch-like syndrome or Breast cancer (Lorca_2019, Dmaso_2020, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer Risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31285513, 32635641, 35534704). ClinVar contains an entry for this variant (Variation ID: 482253). Based on the evidence outlined above, the variant was classified as uncertain significance.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000646329	SCV000844924	uncertain significance	Familial adenomatous polyposis 1	2018-06-01	no assertion criteria provided	clinical testing