Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492007 | SCV000580599 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-06-19 | criteria provided, single submitter | clinical testing | The p.I624S variant (also known as c.1871T>G), located in coding exon 12 of the MSH2 gene, results from a T to G substitution at nucleotide position 1871. The isoleucine at codon 624 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in a family that met Amsterdam II criteria and the colon tumor of the proband displayed high level microsatellite instability (MSI-H) with loss of MSH2 and MSH6 on immunohistochemistry (Ambry internal data). Based on an internal structural assessment, this alteration results in disruption of the sensitive interface between the ATPase and lever domains (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Color Diagnostics, |
RCV000492007 | SCV001351392 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-18 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with serine at codon 624 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 impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in an individual that met Amsterdam II criteria affected with colorectal cancer with high microsatellite instability and loss of MSH2 and MSH6 protein via immunohistochemistry (ClinVar SCV000580599.5). This variant has also been observed in an individual with cancer of unknown primary with a tumor displaying high microsatellite instability and loss of MSH2 protein via immunohistochemistry (PMID: 30376427). 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. |