Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565646 | SCV000669741 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | The p.P696S variant (also known as c.2086C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2086. The proline at codon 696 is replaced by serine, an amino acid with similar properties. This variant has been reported in a patient from Kazakhstan with early onset colorectal cancer (Zhunussova G et al. Front Oncol, 2019 Aug;9:673) and in 2/341 Mexican women identifying as Ashkenazi Jewish, although personal cancer history was not provided (Díaz-Velásquez CE et al. Front Genet, 2023 Feb;14:1094260). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae and was designated "potentially pathogenic" (Ollodart AR et al. Genetics, 2021 Jun;218). Based on internal structural assessment, this alteration results in local destabilization in the ATPase domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000629743 | SCV000750699 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-15 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 696 of the MSH2 protein (p.Pro696Ser). This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Pro696 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 19419416, 23729658, 26053027, 26951660, 27629256, 29731845). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 33357406). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 483672). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). |
| Color Diagnostics, |
RCV000565646 | SCV000912950 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-09 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV004569217 | SCV005053446 | uncertain significance | Lynch syndrome 1 | 2024-02-27 | criteria provided, single submitter | clinical testing |