Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001020600 | SCV001182099 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-10-31 | criteria provided, single submitter | clinical testing | The c.3556+4_3556+8delAGTTT intronic variant, located in intron 6 of the MSH6 gene, results from a deletion of 5 nucleotides within intron 6 of the MSH6 gene. These nucleotide positions are not well 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. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV001860991 | SCV002145768 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-02-19 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 6 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 may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of MSH6-related conditions (Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 823923). 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 skipping of exon 6 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |