Submissions for variant NM_000038.6(APC):c.5378C>G (p.Ala1793Gly)

dbSNP: rs764203580

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218908	SCV000277959	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-23	criteria provided, single submitter	clinical testing	The p.A1793G variant (also known as c.5378C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 5378. The alanine at codon 1793 is replaced by glycine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457479	SCV000552721	uncertain significance	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1793 of the APC protein (p.Ala1793Gly). This variant is present in population databases (rs764203580, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 233560). 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	RCV000457479	SCV000786186	uncertain significance	Familial adenomatous polyposis 1	2018-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797685	SCV002041887	likely benign	not specified	2021-11-14	criteria provided, single submitter	clinical testing	Variant summary: APC c.5378C>G (p.Ala1793Gly) 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 4e-06 in 249802 control chromosomes, however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5378C>G has been reported in the literature in one individual affected with Familial Adenomatous Polyposis (example, Kim_2019), but this report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Additionally, this individual was found to carry a second pathogenic variant (APC c.3577_3578del, p.Gln1193fs), providing supporting evidence for a benign role. Consistently, at-least one additional co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.2731C>T, p.Arg911*) further corroborating an alternative molecular basis of disease and a benign nature of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000218908	SCV002051897	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1793 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 an individual affected with familial adenomatous polyposis (PMID: 34897210). This variant has been identified in 1/249802 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	RCV003126614	SCV003803330	uncertain significance	not provided	2022-08-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with suspected familial adenomatous polyposis (Kim et al., 2019; Park et al., 2022); This variant is associated with the following publications: (PMID: 18199528, 34897210, 31269945)
Myriad Genetics, Inc.	RCV000457479	SCV004019867	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	RCV003998563	SCV004838049	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1793 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 hereditary cancer in the literature. This variant has been identified in 1/249802 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 16 healthy control individuals (PMID: 32980694). 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.
Fulgent Genetics, Fulgent Genetics	RCV005031801	SCV005667865	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-05-04	criteria provided, single submitter	clinical testing