Submissions for variant NM_000535.7(PMS2):c.1501G>A (p.Val501Met)

gnomAD frequency: 0.00004  dbSNP: rs540287433

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588840	SCV000149569	uncertain significance	not provided	2024-06-14	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast or other cancer undergoing multi-gene panel testing (PMID: 31391288, 33471991); This variant is associated with the following publications: (PMID: 26416542, 28577310, 30122538, 29625053, 33471991, 31391288)
Ambry Genetics	RCV000115660	SCV000186841	likely benign	Hereditary cancer-predisposing syndrome	2024-09-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227751	SCV000285073	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 501 of the PMS2 protein (p.Val501Met). This variant is present in population databases (rs540287433, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127762). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001530922	SCV000697299	uncertain significance	not specified	2022-09-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1501G>A (p.Val501Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 403526 control chromosomes, predominantly at a frequency of 7.7e-05 within the Non-Finnish European subpopulation in the gnomAD database (v2.1.1 exomes- and v3.1.2 genomes dataset). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), suggesting that the variant may be a benign polymorphism. However, the variant is located in a region that is highly homologous to a PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.1501G>A, has been reported in the literature as a germline variant in an individual affected with a tumor that belongs to the Lynch syndrome spectrum (Li_2020), and in another individual affected with breast cancer, but was also found in healthy controls (Dorling_2021, through LOVD). In addition, the variant was reported as a somatic occurrence in a Lynch syndrome-associated tumor (Vargas-Parra_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588840	SCV000888394	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The PMS2 c.1501G>A (p.Val501Met) variant has been reported in the published literature in individuals with Lynch Syndrome associated cancer (PMID: 31391288 (2020)), breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)) and in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)).The frequency of this variant in the general population, 0.00007 (8/113710 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000115660	SCV000910743	likely benign	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing
Mendelics	RCV003492486	SCV001137295	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115660	SCV002530197	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000588840	SCV004163707	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PMS2: PM2, BP1, BP4
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005055069	SCV005688986	uncertain significance	Inherited polyposis and early onset colorectal cancer - germline testing	2024-08-15	criteria provided, single submitter	clinical testing	BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359084	SCV005912599	uncertain significance	Lynch syndrome	2024-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742254	SCV005363308	uncertain significance	PMS2-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The PMS2 c.1501G>A variant is predicted to result in the amino acid substitution p.Val501Met. This variant has been identified as a somatic variant in the tumor of an individual with Lynch-like syndrome (Vargas-Parra et al. 2017. PubMed ID: 28577310). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity of likely benign and uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127762/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.