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

gnomAD frequency: 0.00012  dbSNP: rs372297364

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167249	SCV000218089	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.R199C variant (also known as c.595C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 595. The arginine at codon 199 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 1/1260 individuals with a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). 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.
GeneDx	RCV000512735	SCV000279285	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or a Lynch syndrome-associated cancer and/or polyps (PMID: 33471991, 25186627, 25980754); This variant is associated with the following publications: (PMID: 29570743, 25980754, 25589618, 25186627, 29887214, 33471991, 11574484)
Invitae	RCV000233931	SCV000285141	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000410857	SCV000488348	uncertain significance	Lynch syndrome 4	2016-03-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512735	SCV000609250	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167249	SCV000691088	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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	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	2023-09-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)), and suspected Lynch syndrome (PMID: 25980754 (2015)). This variant was also observed in healthy control individuals (PMID: 36243179 (2022)). The frequency of this variant in the general population, 0.00016 (5/30616 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000167249	SCV002530366	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410857	SCV002584607	uncertain significance	Lynch syndrome 4	2022-09-01	criteria provided, single submitter	clinical testing	The PMS2 c.595C>T (p.Arg199Cys) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 including 1 homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000410857	SCV004019784	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003927555	SCV004746402	uncertain significance	PMS2-related disorder	2023-12-06	criteria provided, single submitter	clinical testing	The PMS2 c.595C>T variant is predicted to result in the amino acid substitution p.Arg199Cys. This variant has been reported in a cohort of individuals with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2), and individuals with breast cancer (Tung et al. 2015. PubMed ID: 25186627, supplemental table; reported as chr7_6038849_G_A in supplementary tables, Breast Cancer Association et al. 2021. PubMed ID: 33471991). However, its pathogenicity was not determined with further studies (e.g. segregation, functional assays). This variant has a subpopulation frequency of up to 0.016% in the gnomAD database, including one homozygote and it is reported as likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187514/). Although we suspect that this variant may be benign, 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	RCV000758686	SCV004839955	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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.
True Health Diagnostics	RCV000167249	SCV000886702	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-31	no assertion criteria provided	clinical testing