Submissions for variant NM_000038.6(APC):c.277C>G (p.Leu93Val)

gnomAD frequency: 0.00011  dbSNP: rs201567345

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233150	SCV000282725	likely benign	Familial adenomatous polyposis 1	2025-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000657055	SCV000567833	likely benign	not provided	2020-07-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25980754, 25479140)
Ambry Genetics	RCV000491761	SCV000579800	benign	Hereditary cancer-predisposing syndrome	2015-08-19	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657055	SCV000600064	uncertain significance	not provided	2024-10-29	criteria provided, single submitter	clinical testing	The APC c.277C>G (p.Leu93Val) variant has been reported in the published literature in individuals with suspected Lynch Syndrome (PMID: 25980754 (2015)), breast cancer (PMID: 25186627 (2015)), and pancreatic cancer (PMID: 25479140 (2015)). The frequency of this variant in the general population, 0.00013 (17/129176 chromosomes in European (Non-Finnish) 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000233150	SCV000784803	uncertain significance	Familial adenomatous polyposis 1	2017-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491761	SCV000910848	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818550	SCV002066804	uncertain significance	not specified	2021-01-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.277C>G, in exon 4 that results in an amino acid change, p.Leu93Val. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with a frequency of 0.013% in the European sub-population (dbSNP rs201567345). The p.Leu93Val change affects a moderately conserved amino acid residue located in a domain of the APC protein that is not known to be functional. The p.Leu93Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Leu93Val change remains unknown at this time.
Sema4, Sema4	RCV000491761	SCV002538148	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000233150	SCV002584676	uncertain significance	Familial adenomatous polyposis 1	2022-09-28	criteria provided, single submitter	clinical testing	The APC c.277C>G (p.Leu93Val) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000233150	SCV004019099	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.
All of Us Research Program, National Institutes of Health	RCV003998663	SCV004841717	likely benign	Classic or attenuated familial adenomatous polyposis	2023-12-13	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000491761	SCV005045355	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739625	SCV005360562	uncertain significance	APC-related disorder	2024-04-02	no assertion criteria provided	clinical testing	The APC c.277C>G variant is predicted to result in the amino acid substitution p.Leu93Val. This variant has been identified in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754) as well as in an individual with pancreatic cancer (Table S1, Grant et al. 2015. PubMed ID: 25479140). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/236580/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.