ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1634_1635del (p.Lys545fs) (rs267608064)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129244 SCV000184003 pathogenic Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing ​The c.1634_1635delAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 2 nucleotides at positions 1634 and 1635 causing a translational frameshift with a predicted alternate stop codon (p.K545Rfs*17). This alteration was previously reported in trans with another MSH6 pathogenic mutation in a child with constitutional mismatch repair deficiency (CMMR-D) syndrome (Peters A et al. J. Pediatr. Hematol. Oncol. 2009 Feb;31(2):113-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000202281 SCV000565783 pathogenic not provided 2020-06-15 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015, Ring 2016); This variant is associated with the following publications: (PMID: 26681312, 21674763, 28152038, 25980754, 27443514, 19194194)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202281 SCV000601511 pathogenic not provided 2015-02-26 criteria provided, single submitter clinical testing
Invitae RCV000558194 SCV000624671 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys545Argfs*17) 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 with colorectal cancer (PMID: 26681312) and in an individual with lymphoblastic lymphoma (PMID: 19194194). ClinVar contains an entry for this variant (Variation ID: 140961). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000708867 SCV000837882 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129244 SCV000905450 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000986717 SCV001135809 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202281 SCV000257215 pathogenic not provided no assertion criteria provided research

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