Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002230128 | SCV000551294 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-09-25 | criteria provided, single submitter | clinical testing | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 5 (Invitae). This sequence change falls in intron 4 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 57 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). This variant has been observed in individuals with Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 410528). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1063Arg) have been determined to be pathogenic (PMID: 23733757, 24362816, 26099011, 28531214). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004022787 | SCV005032885 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-01-29 | criteria provided, single submitter | clinical testing | The c.3173-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 5 in the MSH6 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV000460492 | SCV000592624 | uncertain significance | Lynch syndrome | no assertion criteria provided | clinical testing | The MSH6 c.3173-3C>G variant was identified in a sample submitted to the "InSiGHT Colon Cancer Database" within LOVD by an unpublished source. This source remarks that the variant causes a splicing defect of an in-frame deletion of 58 amino acids within exon 5; in addition, the tumour sample showed a loss of MSH6 expression by IHC and high microsatellite instability. The c.3173-3C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in all 5 programs; however, this information is not predictive enough to assume pathogenicity. The variant was not identified in the literature, nor in any other database searches (dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, ClinVar, UMD). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. |