Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000468999 | SCV000548163 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 774 of the MSH2 protein (p.Ile774Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 28765196; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 408475). 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%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 33357406). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000492021 | SCV000580556 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-03 | criteria provided, single submitter | clinical testing | The c.2320A>G variant (also known as p.I774V), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2320. The isoleucine at codon 774 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual who met Bethesda, but not Amsterdam criteria, and had osteosarcoma as well as early-onset, mismatch repair deficient rectal cancer displaying loss of MSH2 and MSH6 on immunohistochemistry (IHC) (de Rosa N et al. J. Clin. Oncol., 2016 Sep;34:3039-46; Borras E et al. Cancer Prev. Res. (Phila.), 2017 Oct;10:580-587). This alteration was also identified in several individuals whose family history met Amsterdam I/II criteria for Lynch syndrome and/or colorectal tumor showed loss of MSH2 protein expression by IHC and/or high microsatellite instability (MSI-H) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Clinical Genetics and Genomics, |
RCV001270006 | SCV001450420 | likely pathogenic | not provided | 2019-05-06 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003463906 | SCV004196831 | likely pathogenic | Lynch syndrome 1 | 2023-05-19 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004000779 | SCV004821070 | uncertain significance | Lynch syndrome | 2023-03-28 | criteria provided, single submitter | clinical testing | |
| Laboratory for Genotyping Development, |
RCV003168800 | SCV002758046 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |