ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.778_780delinsAA (p.Asp260fs) (rs863225398)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474246 SCV000551187 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp390Asnfs*21) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 218051). 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 RCV000202004 SCV000566481 pathogenic not provided 2021-05-12 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 at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32719484)
Ambry Genetics RCV000491518 SCV000580160 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing The c.1168_1170delGATinsAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from the deletion of three nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.D390Nfs*21). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202004 SCV000601503 pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781572 SCV000919726 likely pathogenic Lynch syndrome 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1168_1170delinsAA (p.Asp390AsnfsX21) 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. 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). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121310 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Color Health, Inc RCV000491518 SCV001734833 pathogenic Hereditary cancer-predisposing syndrome 2020-03-09 criteria provided, single submitter clinical testing This variant is located in the MSH6 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202004 SCV000257207 likely pathogenic not provided no assertion criteria provided research

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