Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
University of Washington Department of Laboratory Medicine, |
RCV000758654 | SCV000887419 | uncertain significance | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH2 NM_000251.2:c.2086C>G has a 70.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. |
Color Diagnostics, |
RCV000774580 | SCV000908325 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-06 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001305404 | SCV001494739 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-06-04 | criteria provided, single submitter | clinical testing | 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. 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. 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: 619567). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 696 of the MSH2 protein (p.Pro696Ala). |
Ambry Genetics | RCV000774580 | SCV005033635 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-30 | criteria provided, single submitter | clinical testing | The p.P696A variant (also known as c.2086C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2086. The proline at codon 696 is replaced by alanine, an amino acid with highly similar properties. 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). 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 limited at this time, the clinical significance of this alteration remains unclear. |