ClinVar Genomic variation as it relates to human health

In the published literature, this variant has been reported in an individual affected with pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and as a somatic variant in a head and neck squamous cell carcinoma tumor sample (PMID: 26689913 (2015)). It has been reported in individuals with breast cancer in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). One functional analysis suggested that this variant may retain ATPase and DNA-binding abilities while disrupting the structure of the N-terminal domain, but additional functional studies are needed to ascertain the global effect of this variant on gene and gene product (PMID: 32571878 (2020)). The frequency of this variant in the general population, 0.00008 (10/125392 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 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.

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 34 of the PMS2 protein (p.Ser34Ile). This variant is present in population databases (rs370612538, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, head and neck squamous cell carcinoma, and/or pancreatic ductal adenocarcinoma (PMID: 26689913, 32255556, 34326862). ClinVar contains an entry for this variant (Variation ID: 186945). 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.

This missense variant replaces serine with isoleucine at codon 34 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 an individuals affected with head and neck squamous cell carcinoma (PMID: 26689913) and pancreatic ductal adenocarcinoma (PMID: 32255556). In a large case-control breast cancer study, this variant was reported in 5/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 12/277184 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 serine with isoleucine at codon 34 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 an individuals affected with head and neck squamous cell carcinoma (PMID: 26689913) and pancreatic ductal adenocarcinoma (PMID: 32255556). In a large case-control breast cancer study, this variant was reported in 5/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 12/277184 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.S34I variant (also known as c.101G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide position 101. The serine at codon 34 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was reported in an individual diagnosed with pancreatic ductal adenocarcinoma (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is not well 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.

Variant summary: PMS2 c.101G>T (p.Ser34Ile) results in a non-conservative amino acid change located in the ATPase domain (IPR003594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245786 control chromosomes, predominantly at a frequency of 9.1e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.101G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with pancreatic ductal adenocarcinoma (PDAC) (example, Cremin_2020) and in the The Cancer Genome Atlas (TCGA) cohort (Lu_2015). A large case-control study evaluating breast cancer genetic risk also reported this variant was enriched in the case cohorts (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function (Izuhara_2020). This variant mostly retained the ATPase activity, while lowering affinity for ATP, and destabilized the structure. However, these findings do not allow convincing conclusions about the variant effect in-vivo. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 32255556, 32571878, 26689913, 33471991). ClinVar contains an entry for this variant (Variation ID: 186945). Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed in individuals with personal and/or family history of breast, colorectal, pancreatic and other cancers (PMID: 26689913, 32255556, 33471991, 34326862); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32255556, 26689913, 32571878, 33471991, 11574484, 34326862)