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

gnomAD frequency: 0.00004  dbSNP: rs540287433

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588840	SCV000149569	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or other cancer undergoing multi-gene panel testing (Li et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 31391288, 33471991, 26416542, 28577310, 30122538, 29625053)
Ambry Genetics	RCV000115660	SCV000186841	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-09	criteria provided, single submitter	clinical testing	The p.V501M variant (also known as c.1501G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1501. The valine at codon 501 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000227751	SCV000285073	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 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). 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.
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	2023-08-18	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with a Lynch Syndrome associated cancer (PMID: 31391288 (2020)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). The frequency of this variant in the general population, 0.00007 (8/113710 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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	2016-04-29	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	2023-09-01	criteria provided, single submitter	clinical testing	PMS2: PM2, BP1, BP4