Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076639 | SCV000107674 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Invitae | RCV000822250 | SCV000963043 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-07-13 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the p.Leu187 amino acid residue in MSH2 have been observed in affected individuals (PMID: 18951462, 16327991, 28422960, 17101317, 26951660). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change impairs the mismatch repair activity of the MSH2 protein (PMID: 26951660, 19697156). This variant has been observed in several families affected with Lynch syndrome-associated cancers (PMID: 12624141, 21642682, 16395668, 19697156, 10995807). ClinVar contains an entry for this variant (Variation ID: 91135). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 187 of the MSH2 protein (p.Leu187Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. |
| Ambry Genetics | RCV002345387 | SCV002654158 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-18 | criteria provided, single submitter | clinical testing | The p.L187R variant (also known as c.560T>G), located in coding exon 3 of the MSH2 gene, results from a T to G substitution at nucleotide position 560. The leucine at codon 187 is replaced by arginine, an amino acid with dissimilar properties. This alteration is observed in an individual whose colorectal tumor demonstrated high microsatellite instability and loss of MSH2/MSH6 expression on immunohistochemistry (IHC), and family history met Amsterdam criteria (Christensen LL et al. Fam Cancer, 2009 Aug;8:489-500). This alteration is also observed in an individual whose colorectal tumor demonstrated high microsatellite instability and in 2/537 French Lynch syndrome families (Peel DJ et al. J Natl Cancer Inst, 2000 Sep;92:1517-22; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Functional assays demonstrated deficient MMR activity for p.L187R compared to wild-type MSH2 (Drost M et al. Genet Med, 2019 07;21:1486-1496). Based on internal structural analysis using published crystal structures, L187R disrupts the structure of the MSH6 MutS domain II (Ambry internal data; Warren JJ et al. Mol Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003452951 | SCV004186606 | likely pathogenic | Lynch syndrome 1 | 2023-07-27 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 19697156, 26951660, 16327991, 17101317]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19697156]. |