Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
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Ambry Genetics | RCV000491246 | SCV000580417 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-03-11 | criteria provided, single submitter | clinical testing | The c.1815_1817delTGT variant (also known as p.V606del) is located in coding exon 12 of the MSH2 gene. This variant results from an in-frame TGT deletion between nucleotide positions 1815 and 1817. The valine at codon 606 is deleted. This variant was first identified in a patient who met Bethesda criteria and was diagnosed with endometrial complex atypical hyperplasia (CAH), endometrial adenocarcinoma (EC), and ovarian carcinoma at the age of 50. The patient was also diagnosed with multiple colorectal carcinomas, but the age at each diagnosis was not available. MSI and IHC analysis performed on tumor tissue from CAH and EC showed MSI-H and loss of MSH2 expression with no loss of MLH1 expression (Sutter C et al. Int. J. Gynecol. Pathol. 2004 Jan; 23(1):18-25). This variant was also detected by traditional sequencing techniques as well as SNP genotyping in one patient whose tumor tissue displayed microsatellite instability (Bujalkova M et al. Clin. Chem. 2008 Nov; 54(11):1844-54). The variant is deleterious using an evolution-based in silico predictor, PROVEAN, and this amino acid position is highly conserved in available vertebrate species (Choi Y et al. PLoS ONE 2012;7(10):e46688). Based on internal structural analysis, this variant sits in the lever region of MSH2 and is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell 2007 May; 26(4):579-92 and Mukherjee S et al. Biophys. J. 2009 Mar; 96(5):1707-20). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |