Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000687665 | SCV000815249 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-02-19 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 567547). 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 tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 299 of the MSH2 protein (p.Tyr299Cys). 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000758588 | SCV000887337 | likely benign | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH2 NM_000251.2:c.896A>G has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. |
| Ambry Genetics | RCV001018555 | SCV001179808 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-23 | criteria provided, single submitter | clinical testing | The p.Y299C variant (also known as c.896A>G), located in coding exon 5 of the MSH2 gene, results from an A to G substitution at nucleotide position 896. The tyrosine at codon 299 is replaced by cysteine, an amino acid with highly dissimilar 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. |
| Baylor Genetics | RCV003465561 | SCV004196911 | uncertain significance | Lynch syndrome 1 | 2022-03-24 | criteria provided, single submitter | clinical testing |