Submissions for variant NM_000535.7(PMS2):c.1438G>A (p.Gly480Arg)

gnomAD frequency: 0.00003  dbSNP: rs146848345

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205844	SCV000260965	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). This variant is present in population databases (rs146848345, gnomAD 0.01%). This missense change has been observed in individual(s) with endometrial cancer and/or prostate cancer (PMID: 28873162, 31386297, 34115236, 35449176). ClinVar contains an entry for this variant (Variation ID: 220433). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000219384	SCV000273837	likely benign	Hereditary cancer-predisposing syndrome	2022-10-13	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.
GeneDx	RCV000215100	SCV000279139	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with cancer (Mandelker et al., 2017; Kiyozumi et al., 2019); This variant is associated with the following publications: (PMID: 22949387, 28873162, 31386297)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000215100	SCV000885993	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219384	SCV000911029	likely benign	Hereditary cancer-predisposing syndrome	2016-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780614	SCV000918032	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1438G>A (p.Gly480Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1438G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer. 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. The following publications have been ascertained in the context of this evaluation (PMID: 31386297, 31248605, 34115236). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=2) and VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215100	SCV001134580	uncertain significance	not provided	2023-01-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (4/24958 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 31386297 (2019)), prostate cancer (PMID: 31248605 (2019)), and an unspecified advanced cancer (PMID: 28873162 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000219384	SCV002529795	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491960	SCV004239584	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing