Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076100 | SCV000107122 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
Ambry Genetics | RCV002371916 | SCV002688714 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-05-13 | criteria provided, single submitter | clinical testing | The c.1277-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 8 in the MSH2 gene. This variant has been identified in a proband who met Amsterdam II criteria for Lynch syndrome (Cravo M et al. Gut, 2002 Mar;50:405-12; Lage PA et al. Cancer, 2004 Jul;101:172-7). Other alterations impacting the same acceptor site (c.1277-1G>A and c.1277-2A>G) have been detected in individuals meeting either Amsterdam criteria or Bethesda guidelines for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MSH2 expression by immunohistochemistry (Cravo M et al. Gut, 2002 Mar;50:405-12; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
Myriad Genetics, |
RCV003452819 | SCV004186049 | likely pathogenic | Lynch syndrome 1 | 2023-12-11 | 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. |