ClinVar Genomic variation as it relates to human health

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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.

This missense variant replaces tyrosine with cysteine at codon 103 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant was also shown to cause decreased protein expression, but displayed similar binding to MSH3 and MSH6, as well as comparable homologous recombination and sensitivity to 6-thioguanine to wild type protein in functional studies done in mouse embryonic stem cells (PMID: 21309037). The variant also had no impact on mRNA expression (PMID: 21309037). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 103 of the MSH2 protein (p.Tyr103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862, 35451682). ClinVar contains an entry for this variant (Variation ID: 91061). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 20176959, 21309037, 26951660). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 16995940; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Observed in an individual with a personal and family history of breast cancer and hematologic malignancy (PMID: 34326862); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18383312, 20176959, 16995940, 26951660, 22949387, 21309037, 26333163, 15947132, 18822302, 21120944, 35451682, 33357406, 34326862)

The MSH2 p.Tyr37Cys variant was identified in dbSNP (ID: rs63751173) and ClinVar (classified as a VUS by GeneDx, Counsyl, Ambry Genetics and International Society for Gastrointestinal Hereditary Tumours (InSiGHT) for Lynch syndrome) but was not identified in Cosmic or in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr37 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, 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. Functional assays of the Y37C variant in mouse embryonic stem cells did not reveal a decreased in mismatch repair activity (Wielders_2011_PMID:21309037; Houlleberghs_2016_PMID:26951660). Another functional study of the Y37C variant in S. cerevisiae showed no effect on MMR, but showed an increased mutational rate when found in combination with an MSH6 variant (Martinez_2010_PMID:20176959). 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.