Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076088 | SCV000107103 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
Ambry Genetics | RCV000491760 | SCV000580384 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-29 | criteria provided, single submitter | clinical testing | The c.1276+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 7 of the MSH2 gene. This alteration has been observed in an individual whose colorectal tumor demonstrated high microsatellite instability and loss of MSH2/MSH6 expression on immunohistochemistry (IHC), and family history met Amsterdam criteria (Ambry internal data). This alteration has also been reported in two HNPCC families (Bisgaard ML et al. Hum Mutat, 2002 Jul;20:20-7; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83) and in an individual whose colorectal tumor demonstrated high microsatellite instability and loss of MSH2 expression on IHC (Mangold E et al. J Pathol, 2005 Dec;207:385-95). This alteration was detected in a Danish family with colorectal cancer and was found to segregate with disease within the family (Petersen SM et al. BMC Med Genet, 2013 Oct;14:103). This alteration has also been demonstrated to cause aberrant splicing that leads to an in-frame deletion of 16 amino acids in the MSH6/MSH3 interaction domain of the MSH2 protein (Betz B et al. J Cancer Res Clin Oncol, 2010 Jan;136:123-34; Petersen SM et al. BMC Med Genet, 2013 Oct;14:103). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV000707663 | SCV000836768 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-18 | criteria provided, single submitter | clinical testing | This variant disrupts the c.1276+1G nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15849733, 19669161). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. This sequence change affects a donor splice site in intron 7 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 16 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12112654, 16216036, 18566915, 24090359). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90592). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 7 (PMID: 24090359; Invitae). For these reasons, this variant has been classified as Pathogenic. |
Institute for Clinical Genetics, |
RCV003237437 | SCV002009347 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002498365 | SCV002812380 | likely pathogenic | Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 | 2022-05-31 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV003452816 | SCV004186726 | likely pathogenic | Lynch syndrome 1 | 2023-08-01 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |