Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076750 | SCV000107787 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV000491370 | SCV000580420 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-02 | criteria provided, single submitter | clinical testing | The p.L310P pathogenic mutation (also known as c.929T>C), located in coding exon 5 of the MSH2 gene, results from a T to C substitution at nucleotide position 929. The leucine at codon 310 is replaced by proline, an amino acid with similar properties. This alteration was identified in an individual whose Lynch-related tumor demonstrated loss of MSH2 expression on immunohistochemistry (IHC) and family history met Amsterdam criteria (Ambry internal data). In one study, this variant was detected in an individual diagnosed with rectal cancer at 39 years of age whose tumor showed high microsatellite instability (MSI-H) (Peel DJ et al. J Natl Cancer Inst, 2000 Sep;92:1517-22). In another study, c.929T>C was reported in an individual with MSI-H colon cancer diagnosed prior to 45 years of age; however, the amino acid substitution was reported as p.L310R (Perea J et al. Ann. Surg. Oncol., 2011 Nov;18:3285-91). This alteration was also identified as somatic along with a somatic MSH2 pathogenic mutation in a colon tumor that displayed loss of MSH2 and MSH6 on IHC (Ambry internal data). In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). 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, 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. |
| Invitae | RCV001052685 | SCV001216909 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 310 of the MSH2 protein (p.Leu310Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10995807). ClinVar contains an entry for this variant (Variation ID: 91245). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 33357406). This variant disrupts the p.Leu310 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22290698, 30374176). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |