ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate no damaging effect: similar to wild type in assays assessing RNA and protein expression, viability, apoptosis induction, and DNA damage signaling (PMID: 28494185); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, pancreatic, colon, and/or other cancers, including one who also carried a loss-of-function variant in CHEK2 (PMID: 25186627, 27449771, 29360161, 31391288, 37534630, 38567167); This variant is associated with the following publications: (PMID: 29360161, 25186627, 33471991, 37534630, 27449771, 31391288, 28494185, 38567167)

The p.Ile853Met variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 7/25524 of South Asian chromosom es by the Genome Aggregation DAtabase (gnomAD http://gnomad.broadinstitute.org; dbSNP rs371673459). Computational prediction tools and conservation analysis sug gest that the p.Ile853Met variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, the clinic al significance of the p.Ile853Met variant is uncertain.

In the published literature, the variant has been reported in individuals with pancreatic cancer (PMIDs: 29360161 (2018), 27449771 (2016)) and breast cancer (PMID: 25186627 (2015)). A cell line-based functional study showed this variant has neutral to mild effect on protein expression, cell viability, and DNA damage response signaling (PMID: 28494185 (2017)). The frequency of this variant in the general population, 0.00028 (7/25322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Additional 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.

This missense variant replaces isoleucine with methionine at codon 853 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). A functional study has reported the mutant protein to be functional in response to DNA damaging agents and in phosphorylation of downstream target (PMID: 28494185). This variant has been reported in an individual affected with cancer with features suggestive of Lynch syndrome (PMID: 31391288). This variant has been identified in 24/218728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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 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.

Variant summary: PMS2 c.2559C>G (p.Ile853Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 977138 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome phenotype (7.1e-05), strongly suggesting that the variant is benign. c.2559C>G has been reported in the literature in settings of multigene panel testing (example, Tung_2014, Yang_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Arora_2017). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 25186627, 27449771, 28494185). ClinVar contains an entry for this variant (Variation ID: 142688). Based on the evidence outlined above, the variant was classified as benign.

PMS2: PP2, BP4, BS3:Supporting

Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.