Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076292 | SCV000107313 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability 0.95-0.99 |
| Invitae | RCV001854317 | SCV002155033 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-12-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects MSH2 function (PMID: 30504929, 33357406). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 90791). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18186571). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 603 of the MSH2 protein (p.Asp603Gly). |
| Ambry Genetics | RCV002408595 | SCV002713994 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-10 | criteria provided, single submitter | clinical testing | The p.D603G variant (also known as c.1808A>G), located in coding exon 12 of the MSH2 gene, results from an A to G substitution at nucleotide position 1808. The aspartic acid at codon 603 is replaced by glycine, an amino acid with similar properties. This alteration was detected in a Chinese family meeting Amsterdam criteria for Lynch syndrome and it segregated in three affected family members (Zhang CH et al. World J. Gastroenterol., 2008 Jan;14:298-302). This alteration was also found to have defective mismatch repair activity in a yeast based assay (Arlow T et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Jan;110:246-51). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60).Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV003460714 | SCV004196943 | likely pathogenic | Lynch syndrome 1 | 2021-02-17 | criteria provided, single submitter | clinical testing |