Submissions for variant NM_000038.6(APC):c.6637A>G (p.Met2213Val)

gnomAD frequency: 0.00018  dbSNP: rs186926737

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130848	SCV000185746	benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000236813	SCV000292751	uncertain significance	not provided	2022-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast and Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015; Dutil et al., 2019); This variant is associated with the following publications: (PMID: 25980754, 31780696, 18199528)
Counsyl	RCV000409644	SCV000488390	uncertain significance	Familial adenomatous polyposis 1	2016-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409644	SCV000552775	likely benign	Familial adenomatous polyposis 1	2025-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130848	SCV000681811	likely benign	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV003492605	SCV001136936	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174857	SCV001338247	uncertain significance	not specified	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: APC c.6637A>G (p.Met2213Val) results in a conservative amino acid change in the encoded protein sequence. Five 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 249700 control chromosomes, predominantly at a frequency of 0.00039 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6637A>G has been reported in the literature in at least one individual affected with Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130848	SCV002528820	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409644	SCV004018728	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236813	SCV004219662	likely benign	not provided	2023-04-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905234	SCV004722564	uncertain significance	APC-related disorder	2024-08-25	no assertion criteria provided	clinical testing	The APC c.6637A>G variant is predicted to result in the amino acid substitution p.Met2213Val. This variant has been reported in two individuals undergoing Lynch syndrome testing (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754) and in an individual with breast cancer (Dutil et al. 2019. PubMed ID: 31780696, Table 1). Both studies interpreted this variant as uncertain significance. This variant is reported in 0.050% of alleles in individuals of African descent in gnomAD and is listed in ClinVar as a variant of uncertain significance/likely benign/benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/142044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.