Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000800963 | SCV000940709 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 of the MSH6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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: 26436112; Invitae). ClinVar contains an entry for this variant (Variation ID: 646634). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a premature termination codon (PMID: 26436112; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000826201 | SCV000967755 | pathogenic | Lynch syndrome | 2017-12-05 | criteria provided, single submitter | clinical testing | The c.3556+1G>T variant in MSH6 has been reported in 1 individual with MSH6-asso ciated cancers (Hirotsu 2015) and was absent from large population studies. The c.3556+1G>T variant occurs in the invariant region (+/- 1,2) of the splice conse nsus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that this v ariant causes nonsense mediated decay of MSH6 mRNA and microsatellite instabilit y in tumor sample (Hirotsu 2015). Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. In addition, this varian t was classified as pathogenic on Aug 10, 2016 by the ClinGen-approved InSiGHT e xpert panel (ClinVar SCV000551216.1). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PM2; PS3_Moderate, PS4_Supporting. |
| Gene |
RCV001574493 | SCV001801324 | pathogenic | not provided | 2021-04-27 | criteria provided, single submitter | clinical testing | Canonical splice site variant shown to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Hirotsu 2015); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26436112) |
| Myriad Genetics, |
RCV003453666 | SCV004185540 | likely pathogenic | Lynch syndrome 5 | 2023-08-24 | 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. |
| Laboratory for Genotyping Development, |
RCV003166197 | SCV002758548 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |