Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_000535.7(PMS2):c.505C>G(p.Arg169Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169H) has been classified as Uncertain significance.
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 7-6002485-G-C is Pathogenic according to our data. Variant chr7-6002485-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1745085.Status of the report is criteria_provided_single_submitter, 1 stars.
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 06, 2023
The p.R169G variant (also known as c.505C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 505. The arginine at codon 169 is replaced by glycine, an amino acid with dissimilar properties. This variant has been confirmed in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome (Mork ME et al. Fam Cancer, 2016 10;15:587-91). Based on internal structural analysis, R169G disrupts a conserved arginine mediating a tripartite intramolecular interaction, but there are no internally pathogenic variants nearby for comparison (D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908; Guarné A et al. EMBO J, 2001 Oct;20:5521-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -