Submissions for variant NM_000535.7(PMS2):c.244G>A (p.Gly82Ser)

gnomAD frequency: 0.00001  dbSNP: rs754191682

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232110	SCV000285123	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 82 of the PMS2 protein (p.Gly82Ser). This variant is present in population databases (rs754191682, gnomAD 0.003%). 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: 237909). 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.
Color Diagnostics, LLC DBA Color Health	RCV000447696	SCV000537578	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 82 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with melanoma (PMID: 29684080) and breast cancer (PMID: 32658311). This variant has been identified in 5/282210 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.
Ambry Genetics	RCV000447696	SCV000670755	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The p.G82S variant (also known as c.244G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 244. The glycine at codon 82 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780621	SCV000918044	uncertain significance	not specified	2021-01-27	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.244G>A (p.Gly82Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) 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 250808 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.244G>A has been reported in the literature in individuals affected with Skin Cutaneous Melanoma and Breast Cancer (e.g. Yehia_2018, Akcay_2021). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001549703	SCV001769903	uncertain significance	not provided	2019-06-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30122538)
Sema4, Sema4	RCV000447696	SCV002530310	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001549703	SCV004218990	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000031 (4/128730 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 breast cancer (PMID: 32658311 (2021)) and skin melanoma (PMID: 29684080 (2018)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.