ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3379_3438+5del (rs1553331676)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074844 SCV000108056 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon (also interrupts canonical donor splice site)
GeneDx RCV000214789 SCV000279555 pathogenic not provided 2015-11-11 criteria provided, single submitter clinical testing This deletion of 65 nucleotides in MSH6 is denoted c.3379_3438+5del65 at the cDNA level and p.Ala1127LeufsX15 (A1127LfsX15) at the protein level. The surrounding sequence is CAAA[del65]tgat, where the capital letters are exonic and lowercase are intronic. The deletion causes a frameshift, which changes an Alanine to a Leucine at codon 1127, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation and to destroy a canonical splice donor site resulting in abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MSH6 c.3379_3438+5del65 has been reported in at least one individual with early onset colon cancer and a family history consistent with Lynch syndrome and the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Steinke 2008, Thompson 2014). We consider this variant to be pathogenic.
Ambry Genetics RCV000490849 SCV000580107 pathogenic Hereditary cancer-predisposing syndrome 2017-10-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV001038331 SCV001201797 likely pathogenic Hereditary nonpolyposis colon cancer 2019-11-27 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon(s) 5 (c.3379_3438+5del) of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18301448, Invitae). ClinVar contains an entry for this variant (Variation ID: 89377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000490849 SCV001350203 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-26 criteria provided, single submitter clinical testing

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