Submissions for variant NM_000535.7(PMS2):c.451C>T (p.Arg151Cys)

gnomAD frequency: 0.00001  dbSNP: rs758561884

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221560	SCV000275933	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.R151C variant (also known as c.451C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 451. The arginine at codon 151 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000708999	SCV000838196	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221560	SCV000912097	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 151 of the PMS2 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 reported in an individual affected with epithelial ovarian cancer (PMID: 34350294), and in a large breast cancer case-control study it was observed in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250900 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.
Invitae	RCV000804292	SCV000944195	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 151 of the PMS2 protein (p.Arg151Cys). This variant is present in population databases (rs758561884, gnomAD 0.006%). This missense change has been observed in individual(s) with epithelial ovarian cancer (PMID: 34350294). ClinVar contains an entry for this variant (Variation ID: 231932). 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 expected to disrupt PMS2 protein function. 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.
Sema4, Sema4	RCV000221560	SCV002530346	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282059	SCV002572100	uncertain significance	not specified	2022-08-17	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.451C>T (p.Arg151Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of 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 1.2e-05 in 250900 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.451C>T has been reported in the literature in an individual affected with ovarian cancer (Wu_2021), however this patient also carried a co-occurring (likely) pathogenic variant in BRCA1. This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003401143	SCV004110476	uncertain significance	PMS2-related disorder	2023-01-09	criteria provided, single submitter	clinical testing	The PMS2 c.451C>T variant is predicted to result in the amino acid substitution p.Arg151Cys. This variant has been reported in an individual with breast cancer and individual with epithelial ovarian cancer (Table S8, Li et al. 2019. PubMed ID: 29752822; Table S3, Wu et al. 2021. PubMed ID: 34350294). This variant is reported in 3 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/7-6042170-G-A) and interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/231932/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477737	SCV004219009	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/250900 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer that also had a pathogenic BRCA1 mutation (PMID: 34350294 (2021)). In a large breast cancer association study, the variant was reported in both affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). 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.
All of Us Research Program, National Institutes of Health	RCV000708999	SCV004839972	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 151 of the PMS2 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 reported in an individual affected with epithelial ovarian cancer (PMID: 34350294), and in a large breast cancer case-control study it was observed in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250900 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.