ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3802-7_3802-4del

dbSNP: rs876661171
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219815 SCV000279708 likely pathogenic not provided 2023-10-16 criteria provided, single submitter clinical testing Published RNA studies demonstrate aberrant splicing (Landrith et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31642931, 32133419)
Ambry Genetics RCV000491776 SCV000580092 likely pathogenic Hereditary cancer-predisposing syndrome 2023-09-21 criteria provided, single submitter clinical testing The c.3802-7_3802-4delTCTT intronic variant, located in intron 8 of the MSH6 gene, results from a deletion of 4 nucleotides (TCTT) 7 nucleotides upstream of coding exon 9 in the MSH6 gene. This nucleotide region is well conserved in available vertebrate species. This variant segregated with Lynch syndrome-associated disease in four affected members of one family and has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000491776 SCV000904155 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000801331 SCV000941105 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-05-06 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with Lynch syndrome (PMID: 21520333, 31642931; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000219815 SCV004228229 likely pathogenic not provided 2022-07-28 criteria provided, single submitter clinical testing PP1, PP4, PP5, PM2, PS3_supporting

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