ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3732_3735dup (p.Ser1246fs) (rs1553333072)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486504 SCV000566245 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing This duplication of four nucleotides in MSH6 is denoted c.3732_3735dupATTT at the cDNA level and p.Ser1246IlefsX30 (S1246IfsX30) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CATT[dupATTT]TCAA. The duplication causes a frameshift which changes a Serine to an Isoleucine at codon 1246, and creates a premature stop codon at position 30 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3732_3735dupATTT has been reported in an unaffected individual undergoing multi-gene panel testing due to a family history of cancer (Roberts 2018). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486504 SCV001134440 pathogenic not provided 2019-04-25 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Frequency is consistent with pathogenicity. Seen in at least one patient.
Ambry Genetics RCV001020998 SCV001182556 pathogenic Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV001067391 SCV001232450 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1246Ilefs*30) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 418871). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192493 SCV001360650 likely pathogenic Hereditary nonpolyposis colon cancer 2019-12-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3732_3735dupATTT (p.Ser1246IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251206 control chromosomes (gnomAD). The variant, c.3732_3735dupATTT, has been reported in one unaffected individual who has a family history of cancer (Roberts_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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