Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002428528 | SCV002731876 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-27 | criteria provided, single submitter | clinical testing | The p.T782A variant (also known as c.2344A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2344. The threonine at codon 782 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003098815 | SCV002996246 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-08-07 | criteria provided, single submitter | clinical testing | 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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: 1789912). 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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 782 of the MSH2 protein (p.Thr782Ala). |
| All of Us Research Program, |
RCV004007423 | SCV004827292 | uncertain significance | Lynch syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004526930 | SCV005039016 | uncertain significance | not specified | 2024-03-27 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.2344A>G (p.Thr782Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2344A>G in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. ClinVar contains an entry for this variant (Variation ID: 1789912). Based on the evidence outlined above, the variant was classified as uncertain significance. |