ClinVar Genomic variation as it relates to human health

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. The gain of a new splice site is predicted. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Published functional studies demonstrate a damaging effect on splicing resulting in an abnormal transcript that is subject to nonsense mediated decay (Li et al., 2015; Biswas et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34489406, 34330892, 25691505, 33535600)

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 25691505, 34489406]. Functional studies indicate this variant impacts protein function [PMID: 25691505, 34489406, 30608896]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25691505, 33535600, 30608896, 36586540].

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies in patient derived lymphocytes demonstrated that this missense change generates an alternative splice site at the exon 11–12 junction, resulting in aberrant RNA splicing and the production of a dominant transcript with a 5 base pair deletion that is predicted to lead to nonsense-mediated decay (PMID: 25691505). Further analysis of patient derived samples indicate that a full-length transcript is also produced at low levels resulting in residual expression that may underlie the attenuated CMMRD phenotype that has been reported to be associated with homozygous status of this variant (PMID: 25691505). This variant has been reported to segregate with constitutional mismatch repair deficiency (CMMRD) in several families, and has been shown to be a founder mutation in affected individuals with Inuit ancestry (PMID: 25691505). ClinVar contains an entry for this variant (Variation ID: 192316). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 668 of the PMS2 protein (p.Ile668Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine.

This missense variant replaces isoleucine with valine at codon 668 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). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site 5 nucleotides upstream from the native intron 11 splice donor site. A functional study using cells from a carrier individual has shown that the cryptic donor site is utilized, and the aberrant splicing product results in a premature protein truncation (PMID: 25691505). However, the study also observed small amounts of full-length transcript were also produced from the mutant allele, indicating the leakiness of the cryptic donor site. These full-length transcripts were observed in association with functional partner MLH1 protein. The splicing defect has also been observed in a mouse-model with the mouse equivalent variant, c.1993A>G (PMID: 36715493). This variant occurs at a high frequency in the Canadian Inuit population with estimated heterozygote frequency of 1 in 16 (PMID: 25691505). This study included 13 homozygotes and 38 heterozygotes from 7 unrelated families, where the median age at primary cancer diagnosis associated with constitutional mismatch repair deficiency among the 13 homozygotes was 22 years old. In contrast, the median age of onset is 8 years old in individuals carrying different bi-allelic truncating variants. Another study has shown that affected homozygous carriers had relatively low microsatelite instability (PMID: 36586540). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant occurs at a high frequency in the Inuit population and has been associated with adult-onset cancers in homozygous individuals. However, this variant has not been reported in heterozygous individuals affected with PMS2-related cancers. Presence of the full-length transcript at low levels has been hypothesized as a mechanism for an attenuated phenotype in homozygous individuals. Based on the available evidence, this variant is classified as Likely Pathogenic.