ClinVar Miner

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

gnomAD frequency: 0.00007  dbSNP: rs587779804
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Total submissions: 11
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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)
Invitae RCV003743565 SCV000166049 likely benign Familial adenomatous polyposis 1 2024-02-01 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: 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
Preventiongenetics, part of Exact Sciences RCV003398710 SCV004111318 uncertain significance APC-related condition 2023-09-15 criteria provided, single submitter 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 (http://gnomad.broadinstitute.org/variant/5-112177764-C-G) 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.
Pathway Genomics RCV000122792 SCV000189871 uncertain significance Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing

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