Submissions for variant NM_000038.6(APC):c.6473C>G (p.Pro2158Arg)

gnomAD frequency: 0.00007  dbSNP: rs587779804

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587692	SCV000149021	uncertain significance	not provided	2022-09-29	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: 21859464, 18199528, 27978560, 29148535, 25186627, 26580448, 29684080, 31159747)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122792	SCV000166049	likely benign	Familial adenomatous polyposis 1	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115112	SCV000186636	likely benign	Hereditary cancer-predisposing syndrome	2021-03-09	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235096	SCV000538304	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; Clinvar: 4 vus
Color Diagnostics, LLC DBA Color Health	RCV000115112	SCV000681800	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 2158 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 been observed in individuals affected with colorectal adenomas (PMID: 18199528), colorectal cancer (PMID: 27978560), breast cancer (PMID: 25186627) or referred for hereditary cancer screening (PMID: 31159747). This variant has also been identified in 14/281472 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	RCV000235096	SCV000694095	uncertain significance	not specified	2019-01-07	criteria provided, single submitter	clinical testing	Variant summary: The variant, APC c.6473C>G (p.Pro2158Arg) 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 5e-05 in 278626 control chromosomes (gnomAD and Azzopardi_2008). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.6473C>G has been reported in the literature in individuals affected with colorectal cancer, familial adenomatous polyposis, and breast cancer (Azzopardi_2008, Pearlman_2016, Zhang_2015). However, these reports 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. Six 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.
GeneKor MSA	RCV000115112	SCV000821820	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000122792	SCV001136931	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000122792	SCV001775530	uncertain significance	Familial adenomatous polyposis 1	2021-08-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997227	SCV004840353	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 2158 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 been observed in individuals affected with colorectal adenomas (PMID: 18199528), colorectal cancer (PMID: 27978560), breast cancer (PMID: 25186627) or referred for hereditary cancer screening (PMID: 31159747). This variant has also been identified in 14/281472 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587692	SCV005626369	uncertain significance	not provided	2024-10-09	criteria provided, single submitter	clinical testing	The APC c.6473C>G (p.Pro2158Arg) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 27978560 (2016)), breast cancer (PMID: 25186627 (2015)), and colonic adenomas/polyps (PMID: 34326862 (2021), 18199528 (2008)). This variant has also been observed in a pediatric case of acute myeloid leukemia (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.00012 (3/24288 chromosomes in African/African American 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Pathway Genomics	RCV000122792	SCV000189871	uncertain significance	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398710	SCV004111318	uncertain significance	APC-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The APC c.6473C>G variant is predicted to result in the amino acid substitution p.Pro2158Arg. This variant has been reported in individuals with colorectal adenomas, at least one colon cancer patient with mismatch repair-proficient tumor status (Azzopardi et al. 2008. PubMed ID: 18199528; Pearlman et al. 2017, eTable 2. PubMed ID: 27978560), and patients with a suspected hereditary cancer syndrome (Table S4, Bhai et al. 2021. PubMed ID: 34326862). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is classified as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127313/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.