ClinVar Genomic variation as it relates to human health

Criteria applied: PM2_SUP,PP3

Variant summary: PMS2 c.1999G>A (p.Glu667Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 238424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1999G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with a variety of cancers (example, Kraus_2017, Yang_2016, Sahin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. 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: 27616075, 35089076, 27449771). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 667 of the PMS2 protein (p.Glu667Lys). This variant is present in population databases (rs587780045, gnomAD 0.007%). This missense change has been observed in individual(s) with with PMS2-related conditions (PMID: 27449771, 27616075, 33294277). ClinVar contains an entry for this variant (Variation ID: 127769). 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.

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with peritoneal or other cancers undergoing multigene hereditary cancer testing (PMID: 27616075, 31159747, 35089076, 31391288); This variant is associated with the following publications: (PMID: 31159747, 33294277, 31391288, 35089076, 11292842, 27616075)

This missense variant replaces glutamic acid with lysine at codon 667 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with peritoneal cancer (PMID: 27616075), head and neck squamous cell carcinoma (PMID: 26689913), breast cancer (PMID: 35127508, 36011273; Duzkale et al. 2021), and colorectal cancer with a tumor showing MSH6 loss via immunohistochemistry but microsatellite stability (PMID: 33294277). This variant has been identified in 8/238424 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.

This missense variant replaces glutamic acid with lysine at codon 667 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with peritoneal cancer (PMID: 27616075), colorectal cancer with immunohistochemistry showing MSH6 loss (PMID: 33294277), head and neck squamous cell carcinoma (PMID: 26689913), and breast cancer (PMID: 35127508, 36011273; Duzkale et al. 2021). This variant has been identified in 8/238424 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.

The p.E667K variant (also known as c.1999G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1999. The glutamic acid at codon 667 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals diagnosed with peritoneal, colon, and pancreatic cancers (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Xu HX et al. Am J Cancer Res. 2020 Nov;10:3920-3934; Yang XR et al. Hum Genet. 2016 Nov;135:1241-1249). This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). 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.

The PMS2 c.1999G>A variant is predicted to result in the amino acid substitution p.Glu667Lys. This variant has been reported as a variant of uncertain significance in individuals affected with peritoneal cancer (Kraus et al. 2017. PubMed ID: 27616075), colorectal cancer (Xu et al. 2020. PMID: 33294277), breast and/or ovarian cancer (Tsaousis et al. 2019. PubMed ID: 31159747; Li et al. 2019. PubMed ID: 31391288). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127769/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.