Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000168245 | SCV000218915 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 319 of the MSH2 protein (p.Asp319Val). This variant is present in population databases (rs786204185, gnomAD 0.06%). 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: 188267). 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. |
| Ambry Genetics | RCV001019487 | SCV001180851 | likely benign | Hereditary cancer-predisposing syndrome | 2022-06-13 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Color Diagnostics, |
RCV001019487 | SCV002053630 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with valine at codon 319 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 30093976). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Sema4, |
RCV001019487 | SCV002526779 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-17 | criteria provided, single submitter | curation | |
| All of Us Research Program, |
RCV003995617 | SCV004824432 | uncertain significance | Lynch syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with valine at codon 319 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 30093976). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |