Submissions for variant NM_000535.7(PMS2):c.751G>A (p.Val251Met)

gnomAD frequency: 0.00003  dbSNP: rs142434011

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587187	SCV000211574	uncertain significance	not provided	2022-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with early-onset colorectal cancer (Zhunussova et al., 2019); This variant is associated with the following publications: (PMID: 31428572, 11574484)
Invitae	RCV000206870	SCV000261020	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	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 251 of the PMS2 protein (p.Val251Met). This variant is present in population databases (rs142434011, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 31428572). ClinVar contains an entry for this variant (Variation ID: 182801). 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 expected to disrupt PMS2 protein function with a positive 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587187	SCV000601859	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000031 (4/128504 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 31428572 (2019)). 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.
Ambry Genetics	RCV000567432	SCV000663424	likely benign	Hereditary cancer-predisposing syndrome	2022-08-29	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.
Color Diagnostics, LLC DBA Color Health	RCV000567432	SCV000686234	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 251 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 early onset colorectal cancer (PMID: 31428572). This individual also carried a pathogenic variant in the MUTYH gene that could explain the observed phenotype. This variant has been identified in 6/281164 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	RCV000160885	SCV000697384	uncertain significance	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.751G>A (p.Val251Met) results in a conservative amino acid change located in the N-terminal (IPR002099) and S5 domain 2-like (IPR013507) domains of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250208 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.751G>A has been reported in the literature in at least one individual affected with early onset colorectal cancer (Zhunussova_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. A co-occurrence with a pathogenic variant has been reported through internal testing (CHEK2 c.1100delC, p.Thr367MetfsX15). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160885	SCV002550740	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462102	SCV004205335	uncertain significance	Lynch syndrome 4	2023-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927529	SCV004738146	likely benign	PMS2-related disorder	2022-03-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003998523	SCV004839920	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 251 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 early onset colorectal cancer (PMID: 31428572). This individual also carried a pathogenic variant in the MUTYH gene that could explain the observed phenotype. This variant has been identified in 6/281164 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	RCV000567432	SCV000805284	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing