ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3542_3545dup (p.Ile1183fs) (rs267608127)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074951 SCV000108166 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000479887 SCV000568733 pathogenic not provided 2016-03-28 criteria provided, single submitter clinical testing This duplication of 4 nucleotides in MSH6 is denoted c.3932_3935dupAAGT at the cDNA level and p.Ile1313SerfsX7 (I1313SfsX7) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GAGG[AAGT]TATT. The duplication causes a frameshift which changes an Isoleucine to a Serine at codon 1313, and creates a premature stop codon at position 7 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 48 amino acids are no longer translated correctly, and it is predicted to cause loss of normal protein function through protein truncation. This variant disrupts an MSH2 binding site in domain V of the MutS domain (Kariola 2002, Terui 2013). MSH6 c.3932_3935dupAAGT, also known as c.3932_3935dup4 using alternative nomenclature, has been observed in at least two individuals from a single family, one of whom had a diagnosis of colorectal or endometrial cancer (Ramsoekh 2008). The adjacent variant MSH6 c.3934_3937dupGTTA, which also results in a frameshift at this residue (p.Ile1313SerfsX7), has been observed in at least two other individuals with a clinical history of a Lynch syndrome associated cancer and/or colon polyps, one of whom was also diagnosed with breast cancer (Susswein 2015, Yurgelun 2015). Based on currently available evidence, we consider this variant to be pathogenic.

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