ClinVar

Description

The MSH2 p.Thr33Pro variant was identified in 3 of 2424 proband chromosomes (frequency: 0.001) from individuals with colon and endometrial cancer (Hegde 2005, Hampel 2006, Chubb 2015). The variant was identified in dbSNP (rs63751107) as “with uncertain significance allele”, ClinVar (classified as "uncertain significance" by Invitae, GeneDx and five other submitters) and UMD-LSDB (observed 2x). The variant was identified in control databases in 14 of 248,976 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 4 of 31,200 chromosomes (freq: 0.0001), European in 10 of 113,324 chromosomes (freq: 0.00009), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. A cell line derived from a patient with the observed variant had normal levels of MSH2 and MSH6 protein as observed on a western blot (Ollila 2006). In an in vitro mismatch repair assay, the variant was generated by site-directed mutagenesis and decreased MMR efficiency by 23% compared to wild type (Ollila 2006). The variant is present in the DNA binding domain of MSH2 and in another study was demonstrated to bind mismatches as efficiently as wild type, and had a slightly reduced DNA release. These observations led to the conclusion that the variant causes a slight defect in MMR efficiency, and based on these experiments, it is unclear if the variant is pathogenic (Ollila 2008). The p.Thr33 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.