Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001024745 | SCV001186820 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-05-30 | criteria provided, single submitter | clinical testing | The p.C199W variant (also known as c.597T>G), located in coding exon 3 of the MSH2 gene, results from a T to G substitution at nucleotide position 597. The cysteine at codon 199 is replaced by tryptophan, an amino acid with highly dissimilar properties. Two other alterations at the same amino acid position, p.C199Y and p.C199R, have been reported as likely pathogenic and pathogenic, respectively, based on functional studies as well as identification in individuals whose tumors displayed absent MSH2 expression on immunohistochemistry (IHC) and family histories met Amsterdam criteria for Lynch syndrome (Gammie AE et al. Genetics. 2007;177(2):707-21; Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739; Ewald J et al. Br J Surg, 2007 Aug;94:1020-7; Leung SY et al. Am J Pathol. 1998;153(4):1181-8; Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6; Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Gupta S et al. Nat. Struct. Mol. Biol., 2011 Dec;19:72-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |