Submissions for variant NM_000038.6(APC):c.1241G>A (p.Arg414His)

gnomAD frequency: 0.00003  dbSNP: rs730881233

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159530	SCV000209490	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with neuroblastoma and in an individual with osteosarcoma (Zhang et al., 2015; Mirabello et al., 2020); This variant is associated with the following publications: (PMID: 32231684, 26580448, 32191290)
Invitae	RCV003315945	SCV000282692	uncertain significance	Familial adenomatous polyposis 1	2024-02-01	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 414 of the APC protein (p.Arg414His). This variant is present in population databases (rs730881233, gnomAD 0.02%). This missense change has been observed in individual(s) with neuroblastoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 181785). 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.
Counsyl	RCV000227001	SCV000489182	uncertain significance	Familial adenomatous polyposis 1	2016-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568544	SCV000667237	likely benign	Hereditary cancer-predisposing syndrome	2021-05-26	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.
PreventionGenetics, part of Exact Sciences	RCV000159530	SCV000805366	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568544	SCV000905879	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 414 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 8/250586 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	RCV000779739	SCV000916511	uncertain significance	not specified	2018-11-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.1241G>A (p.Arg414His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245360 control chromosomes, predominantly at a frequency of 0.00021 within the Latino subpopulation in the gnomAD database, which is 3-folds over the estimated maximum expected allele frequency for a pathogenic APC variant. Therefore, suggesting the variant is a benign polymorphism found predominantly in population(s) of Latino origin. c.1241G>A has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159530	SCV002046700	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568544	SCV002533724	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002484993	SCV002779495	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-03-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315945	SCV004018744	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.
Baylor Genetics	RCV000227001	SCV004197708	uncertain significance	Familial adenomatous polyposis 1	2023-10-24	criteria provided, single submitter	clinical testing