Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001027174 | SCV001189687 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-27 | criteria provided, single submitter | clinical testing | The p.L270P pathogenic mutation (also known as c.809T>C), located in coding exon 5 of the MSH2 gene, results from a T to C substitution at nucleotide position 809. The leucine at codon 270 is replaced by proline, an amino acid with similar properties. This alteration was reported once in a cohort study of 59 families from Singapore that either met Amsterdam I/II or Japanese criteria for Lynch syndrome (Liu Y et al. PLoS ONE 2014 Apr;9:e94170). This alteration was also identified in a proband whose Lynch-associated tumor demonstrated loss of MHS2 and MSH6 staining on immunohistochemistry (Ambry internal data). 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 01;108:163-175). Based on an internal structural analysis using published crystal structures, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Gupta S et al. Nat Struct Mol Biol, 2011 Dec;19:72-8). This variant is considered to be rare based on population 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV001066735 | SCV001231752 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-07-08 | criteria provided, single submitter | clinical testing | 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 827451). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 24710284). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 270 of the MSH2 protein (p.Leu270Pro). |
| Myriad Genetics, |
RCV003455140 | SCV004186745 | likely pathogenic | Lynch syndrome 1 | 2023-07-28 | 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: 33357406] |