ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1190_1191del (p.Tyr397fs) (rs63750439)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160740 SCV000580232 pathogenic Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000497288 SCV000211379 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in MSH6 is denoted c.1190_1191delAT at the cDNA level and p.Tyr397CysfsX3 (Y397CfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCT[delAT]GTGC. The deletion causes a frameshift, which changes a Tyrosine to a Cysteine at codon 397, and creates a premature stop codon at position 3 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.1190_1191delAT has been observed in individuals with early-onset colon cancer who had tumors showing microsatellite instability (Plaschke 2004, Steinke 2008, You 2010). We consider this variant to be pathogenic. This deletion of two nucleotides in MSH6 is denoted c.1190_1191delAT at the cDNA level and p.Tyr397CysfsX3 (Y397CfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCT[delAT]GTGC. The deletion causes a frameshift which changes a Tyrosine to a Cysteine at codon 397, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH6 Tyr397CysfsX3 has been LIT SUMMARY. We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074640 SCV000919727 pathogenic Lynch syndrome 2017-11-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1190_1191delAT (p.Tyr397CysfsX3) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1444C>T (p.Arg482X), c.1572C>A (p.Tyr524X), c.1634_1637delAAGA (p.Lys545fsX25)). The variant has been observed in patients with HNPCC-associated cancers (i.e. CRC and cancer of the endometrium), in one of them a CRC tumor sample showing loss of MSH6 and microsatellite instability (Plaschke 2004, Susswein 2015). This variant was found in 2/245974 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074640 SCV000107842 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000497288 SCV000691923 pathogenic not provided no assertion criteria provided clinical testing

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