ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.595C>T (p.Arg199Cys) (rs372297364)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167249 SCV000218089 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000512735 SCV000279285 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.595C>T at the cDNA level, p.Arg199Cys (R199C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in at least one individual undergoing multi-gene cancer panel testing based on the presence of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). PMS2 Arg199Cys was observed at an allele frequency of 0.016% (5/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). PMS2 Arg199Cys is located in the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg199Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233931 SCV000285141 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 199 of the PMS2 protein (p.Arg199Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372297364, ExAC 0.01%). This variant has been reported in the literature in individuals with suspected Lynch syndrome (PMID: 25980754) and with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 187514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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 RCV000410857 SCV000488348 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-03-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512735 SCV000609250 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Color RCV000167249 SCV000691088 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722125 SCV000697374 likely benign not specified 2018-04-19 criteria provided, single submitter clinical testing Variant summary: PMS2 c.595C>T (p.Arg199Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277240 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.41 folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. In addition, the location of this variant in exon 6 is a region specific to the PMS2 gene with no indicated homology to the PMS2 pseudogene. The variant, c.595C>T, has been reported in the literature in individuals affected with Lynch Syndrome (Tung_2015, Yurgelun_2015). These report(s) do 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758686 SCV000887458 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.595C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000512735 SCV000889633 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000167249 SCV000886702 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 no assertion criteria provided clinical testing

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