ClinVar

Description

The MSH2 p.Val273Ile variant was identified in dbSNP (ID: rs530814648) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (2x), and not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 8 of 245604 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), with breakdown of the observations by population include European Non-Finnish in 1 of 111478 chromosomes (freq: 0.000009) and South Asian in 7 of 30496 chromosomes (freq: 0.0002) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian and European Finnish, populations. The variant was also identified by our laboratory in 1 individual with endometrial cancer, co-occurring with a pathogenic MLH1 variant (c.588+1G>C). The p.Val273 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. RNA analysis (RT-PCR and allele specific RT-PCR) of peripheral blood RNA, on a cohort of patients with unclassified variants showed that the MSH2 c.817G>A;c.817T>A/p.Val274Lys was associated with normal RNA expression and splicing (Sharp_2004_ 15300854). 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 benign role for this variant. This variant is classified as likely benign.