Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076614 | SCV000107650 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability between 0.95-0.99 |
| Invitae | RCV000630010 | SCV000750966 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with aspartic acid at codon 165 of the MSH2 protein (p.Tyr165Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with Lynch syndrome (PMID: 24501230), as well as families with suspected Lynch syndrome (PMID: 24501230, Invitae). ClinVar contains an entry for this variant (Variation ID: 91111). Experimental studies have shown that this missense change results in reduced MSH2 and MSH6 protein expression (PMID: 24501230, 26951660) and disrupted mismatch repair activity (PMID: 22102614, 24501230, 26951660). 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. |
| Color Diagnostics, |
RCV003584547 | SCV004356600 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-14 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with aspartic acid at codon 165 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies showed that the variant protein is defective in an in vitro DNA mismatch repair assay (PMID: 22102614) and fully to partially defective in 6-thioguanine sensitivity assays (PMID: 24501230, 33357406), and partially to fully defective in mutator phenotype and MNNG-sensitivity assays (PMID: 24501230). This variant has been reported in three individuals from two unrelated families affected with colorectal cancer that showed microsatellite instability (PMID: 24501230) and individual or family suspected to be affected with Lynch syndrome (PMID: 22102614). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |