ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3660_3663dup (p.Phe1222fs) (rs752404604)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492020 SCV000580324 pathogenic Hereditary cancer-predisposing syndrome 2016-02-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000588486 SCV000695882 likely pathogenic Lynch syndrome 2019-05-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3660_3663dupAACA (p.Phe1222AsnfsX3) 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 (eg. c.3699_3702delAGAA (p.Lys1233fsX6), c.3799_3800delAT (p.Met1267fsX7)). The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3660_3663dupAACA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One other submitter have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000799829 SCV000939511 pathogenic Hereditary nonpolyposis colon cancer 2019-11-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1222Asnfs*3) 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 considered unreliable, as metrics indicate poor data quality at this position 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: 428406). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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