Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000572655 | SCV000662258 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-22 | criteria provided, single submitter | clinical testing | The p.R214K variant (also known as c.641G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 641. The arginine at codon 214 is replaced by lysine, 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 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001858104 | SCV002270726 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 214 of the MSH2 protein (p.Arg214Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 479795). 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 with a negative predictive value of 80%. 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. |
| All of Us Research Program, |
RCV004000852 | SCV004822788 | uncertain significance | Lynch syndrome | 2022-11-28 | criteria provided, single submitter | clinical testing |