ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3753_3756dupATTA (p.Val1253Ilefs) (rs876661222)

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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 RCV000566381 SCV000662520 pathogenic Hereditary cancer-predisposing syndrome 2016-09-27 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)
Counsyl RCV000576807 SCV000677835 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-01-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502952 SCV000592655 pathogenic Lynch syndrome 2015-09-25 criteria provided, single submitter clinical testing
GeneDx RCV000216513 SCV000279830 pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing This duplication of four nucleotides in MSH6 is denoted c.3753_3756dupATTA at the cDNA level and p.Val1253IlefsX23 (V1253IfsX23) at the protein level. The normal sequence, with the bases that are duplicated in braces, is ATTC[ATTA]GTAG. The duplication causes a frameshift, which changes a Valine to an Isoleucine at codon 1253, and creates a premature stop codon at position 23 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.
Invitae RCV000690322 SCV000818004 pathogenic Hereditary nonpolyposis colon cancer 2018-05-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1253Ilefs*23) 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 disease. ClinVar contains an entry for this variant (Variation ID: 234794). 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 RCV000502952 SCV000837921 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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