Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000630179 | SCV000751135 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-30 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 783 of the MSH2 protein (p.His783Tyr). 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: 525836). 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 | RCV003362867 | SCV004055856 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-09 | criteria provided, single submitter | clinical testing | The p.H783Y variant (also known as c.2347C>T), located in coding exon 14 of the MSH2 gene, results from a C to T substitution at nucleotide position 2347. The histidine at codon 783 is replaced by tyrosine, an amino acid with 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 | RCV003459500 | SCV004196876 | uncertain significance | Lynch syndrome 1 | 2023-01-23 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004002794 | SCV004819935 | uncertain significance | Lynch syndrome | 2023-06-15 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with tyrosine at codon 783 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 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. |