Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000160598 | SCV000211194 | uncertain significance | not provided | 2020-10-28 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Invitae | RCV000203996 | SCV000261679 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 681 of the MSH2 protein (p.Gln681Glu). This variant is present in population databases (rs730881762, gnomAD 0.0009%). 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: 182568). 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 | RCV001014194 | SCV001174876 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing | The p.Q681E variant (also known as c.2041C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2041. The glutamine at codon 681 is replaced by glutamic acid, 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. |
Baylor Genetics | RCV003467249 | SCV004196328 | uncertain significance | Lynch syndrome 1 | 2023-08-05 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001014194 | SCV004356721 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-27 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with glutamic acid at codon 681 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251456 chromosomes 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. |
All of Us Research Program, |
RCV003998476 | SCV004832341 | uncertain significance | Lynch syndrome | 2023-08-28 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with glutamic acid at codon 681 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251456 chromosomes 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. |