Submissions for variant NM_000038.6(APC):c.8141G>A (p.Arg2714His)

gnomAD frequency: 0.00002  dbSNP: rs747362422

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457741	SCV000552655	uncertain significance	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2714 of the APC protein (p.Arg2714His). This variant is present in population databases (rs747362422, gnomAD 0.01%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 411478). 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%. 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.
GeneDx	RCV000759449	SCV000564586	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30981987, 22510280, 27882345, 28188106, 31202631, 29338072, 18199528, 25980754)
Ambry Genetics	RCV000571502	SCV000667220	benign	Hereditary cancer-predisposing syndrome	2021-02-09	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.
Mendelics	RCV000457741	SCV000838160	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759449	SCV000888775	uncertain significance	not provided	2020-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571502	SCV000903029	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2714 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 APC-related disorders in the literature. This variant has been identified in 9/282714 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706640	SCV001821347	uncertain significance	not specified	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: APC c.8141G>A (p.Arg2714His) results in a non-conservative amino acid change located in the EB-1 binding (IPR009232) of 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 251318 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8141G>A has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual affected with colorectal cancer (example, Yurgelun_2015). These report(s) do 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=6). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000571502	SCV002531592	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004001957	SCV004835767	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2714 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 APC-related disorders in the literature. This variant has been identified in 9/282714 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000571502	SCV005045376	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing