Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001010702 | SCV001170935 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-03-24 | criteria provided, single submitter | clinical testing | The c.1276G>C variant (also known as p.G426R), located in coding exon 7 of the MSH2 gene, results from a G to C substitution at nucleotide position 1276. The amino acid change results in glycine to arginine at codon 426, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in an individual with colorectal cancer (CRC) diagnosed at age 28 years and a metachronous CRC at 44 years; this individual had two additional family members with Lynch syndrome cancers who tested positive for this alteration (Thodi G et al. BMC Cancer 2010 Oct;10:544). This alteration has also been detected in an individual with colorectal cancer diagnosed previous to age 50 years, with concordant immunohistochemistry showing loss of MSH2/MSH6 (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV003336230 | SCV004043202 | likely pathogenic | Lynch syndrome 1 | 2023-09-28 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28577310, 35676339]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Invitae | RCV003594068 | SCV004293887 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-11-19 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 818775). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20937110). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the MSH2 protein (p.Gly426Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. |