ClinVar Genomic variation as it relates to human health

The p.S46N variant (also known as c.137G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 137. The serine at codon 46 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified likely in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome, whose Lynch syndrome-associated tumor and normal tissue demonstrated loss of PMS2 expression by immunohistochemistry; the tumor also displayed high frequency microsatellite instability (Jackson CC et al. Pediatr Blood Cancer 2008 Jun; 50(6):1268-70). In an in vitro study, this alteration displayed less than 10% relative repair efficiency compared to the wild-type control, a level similar to the repair-deficient control (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). Based on internal structural analysis, p.S46N is more disruptive to the structure near the ATP-binding region than a pathogenic variant at the same position (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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.

This missense variant replaces serine with asparagine at codon 46 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). A functional study has shown that this variant protein causes significantly decreased mismatch repair activity in an in vitro assay (PMID: 24027009). This variant has been reported in an individual with sebaceous neoplasm and family history of colorectal cancer (PMID: 25006859) and in multiple other individuals with personal and family history of Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000552059.6, SCV002699807.1). This variant has been observed in an individual affected with constitutional mismatch repair deficiency in compound heterozygous state with another disease-causing variant in the same gene (PMID: 18273873). In addition, a different variant affecting the same codon (p.Ser46Ile) is considered to be disease-causing (ClinVar variation ID: 9245), suggesting that serine at this position is important for PMS2 protein function. This variant has been identified in 2/245780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 46 of the PMS2 protein (p.Ser46Asn). This variant is present in population databases (rs121434629, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 18273873, 25006859, 26866578; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91301). 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%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 24027009). This variant disrupts the p.Ser46 amino acid residue in PMS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22577899, 23709753). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24027009]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25006859, 18602922, 18273873].

Observed in a patient with a personal history of a sebaceous adenoma and a family history of colon cancer (PMID: 25006859); Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (PMID: 24027009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34873870, 33259954, 28125078, 25871441, 26940435, 9607916, 18602922, 26866578, 21182953, 31992580, 31658756, 30155321, 28286799, 22577899, 21239990, 21376568, 18094436, 16144131, 25006859, 18273873, 24027009, 11574484)

The PMS2 p.Ser46Asn variant was identified in 2 of 370 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Senter 2008, Everett 2014). The variant was also identified in dbSNP (ID: rs121434629) as "With Pathogenic allele", ClinVar (classified as uncertain significance by InSight; as likely pathogenic by Invitae; and as pathogenic by Mayo Clinic), GeneInsight-COGR, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors database (4x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 2 of 240416 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 107732 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser46 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant was reported as a biallelic gene mutation, identified with the PMS2 c.137G>T mutation in an individual with sigmoid adenocarcinoma; the tumour had high microsatellite instability and both the tumour and normal tissue were PMS2-deficient on IHC (Jackson 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.