Submissions for variant NM_000038.6(APC):c.764A>G (p.His255Arg)

gnomAD frequency: 0.00001  dbSNP: rs530670052

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563264	SCV000282829	uncertain significance	Familial adenomatous polyposis 1	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 255 of the APC protein (p.His255Arg). This variant is present in population databases (rs530670052, gnomAD 0.004%). This missense change has been observed in individual(s) with gastrointestinal cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 236648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000574604	SCV000672528	likely benign	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000574604	SCV000911222	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 255 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 prostate cancer (PMID: 32268276). This variant has been identified in 4/251096 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	RCV001192799	SCV001361158	uncertain significance	not specified	2019-09-12	criteria provided, single submitter	clinical testing	Variant summary: APC c.764A>G (p.His255Arg) results in a non-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 1.6e-05 in 251096 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.764A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have 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 uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003401163	SCV004118814	uncertain significance	APC-related disorder	2023-08-18	criteria provided, single submitter	clinical testing	The APC c.764A>G variant is predicted to result in the amino acid substitution p.His255Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112137010-A-G) and is listed in ClinVar with conflicting interpretations of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/236648/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003998691	SCV004837317	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 255 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 prostate cancer (PMID: 32268276). This variant has been identified in 4/251096 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192799	SCV005090674	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001699072	SCV005623617	uncertain significance	not provided	2024-08-16	criteria provided, single submitter	clinical testing	The APC c.764A>G (p.His255Arg) variant has been reported in the published literature in reported in individuals with suspected hereditary cancer syndrome (PMID: 34326862 (2021)) and metastatic prostate cancer (PMID: 32268276 (2020)). The frequency of this variant in the general population, 0.000035 (4/113570 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Clinical Genetics, Academic Medical Center	RCV001699072	SCV001917200	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699072	SCV001954725	likely benign	not provided		no assertion criteria provided	clinical testing