ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1168_1170delinsAA (p.Asp390fs) (rs863225398)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491518 SCV000580160 pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 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 RCV000202004 SCV000566481 pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted MSH6 c.1168_1170delGATinsAA at the cDNA level and p.Asp390AsnfsX21 (D390NfsX21) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is CCC[GAT][AA]TTTG. The variant causes a frameshift, which changes an Aspartic Acid to an Asparagine at codon 390, and creates a premature stop codon at position 21 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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000474246 SCV000551187 pathogenic Hereditary nonpolyposis colon cancer 2018-12-22 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. This variant is present in population databases (rs753796271, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related conditions. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202004 SCV000257207 likely pathogenic not provided no assertion criteria provided research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202004 SCV000601503 pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing

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