ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.962del (p.Phe321fs) (rs869312769)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210100 SCV000266089 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000684808 SCV000551304 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe451Serfs*2) 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 the literature in an individual affected with small intestine cancer and polyposis (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224534). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000480743 SCV000571367 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH6 is denoted c.1352delT at the cDNA level and p.Phe451SerfsX2 (F451SfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is GTAT[T]CATG. The deletion causes a frameshift which changes a Phenylalanine to a Serine at codon 451, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics RCV000490853 SCV000580124 pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000210100 SCV001338278 likely pathogenic Lynch syndrome 2020-02-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1352delT (p.Phe451SerfsX2) 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 was absent in 251008 control chromosomes (gnomAD). c.1352delT has been reported in the literature in at least one individual affected with small intestine cancer and polyposis (Shirts_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (4x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color RCV000490853 SCV001346913 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000480743 SCV000691926 likely pathogenic not provided no assertion criteria provided clinical testing

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