Submissions for variant NM_000535.7(PMS2):c.475G>A (p.Val159Met)

gnomAD frequency: 0.00004  dbSNP: rs142416537

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235195	SCV000149605	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal, breast, prostate, or stomach cancer (Chubb et al., 2015; Lu et al., 2015; Haraldsdottir et al., 2017; Yehia et al., 2018; Stuttgen et al., 2019; Akcay et al., 2020; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 25559809, 26689913, 28466842, 29684080, 28873162, 29354287, 31391288, 31465090, 11574484, 32832836, 32658311)
Invitae	RCV000123087	SCV000166387	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115696	SCV000184308	likely benign	Hereditary cancer-predisposing syndrome	2022-12-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000115696	SCV000686207	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 159 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 25559809), stomach adenocarcinoma (PMID: 26689913), and breast cancer (PMID: 26689913, 29684080, 31465090). This variant has been identified in 17/245638 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.
Mendelics	RCV000708998	SCV000838195	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765968	SCV000897389	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000987848	SCV001137323	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235195	SCV001470601	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMIDs: 25559809 (2015), 28466842 (2017)), stomach adenocarcinoma (PMIDs: 26689913 (2015)), and breast cancer (PMIDs: 32658311 (2021), 26689913 (2015), 31465090 (2019)). In a large breast cancer association study, the variant was reported in both cases and controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.00012 (16/128726 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465515	SCV002760384	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000987848	SCV004042771	uncertain significance	Lynch syndrome 4	2023-02-20	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PS4_MOD, PM2_SUP, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000235195	SCV004185426	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987848	SCV004205465	uncertain significance	Lynch syndrome 4	2023-08-31	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115696	SCV004228037	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952550	SCV004778286	uncertain significance	PMS2-related condition	2024-01-29	criteria provided, single submitter	clinical testing	The PMS2 c.475G>A variant is predicted to result in the amino acid substitution p.Val159Met. This variant was reported as a variant of uncertain significance in an individual with breast cancer (Stuttgen et al. 2019. PubMed ID: 31465090) and was also reported in cohorts of individuals with colorectal cancer (Chubb et al. 2015. PubMed ID: 25559809, Table A1; Haraldsdottir et al. 2017. PubMed ID: 28466842). Additionally, this variant was reported in an individual with stomach adenocarcinoma (Lu et al. 2015. PubMed ID: 26689913, supplementary table 12) and in a cohort of individuals with cancer (Yehia et al. 2018. PubMed ID: 29684080, Table S9). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In the ClinVar database, this variant has been listed as 'uncertain' or 'likely benign' by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/127791/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355954	SCV001550987	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Val159Met variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in dbSNP (ID: rs142416537) “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (4x), Insight Hereditary Tumors Database (1x), and in control databases in 17 of 245638 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 16 of 111290 chromosomes (freq: 0.0001), European Finnish in 1 of 22242 chromosomes (freq: 0.00005), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val159 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Met to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.