ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3850dup (p.Thr1284fs) (rs1553333421)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501318 SCV000592657 pathogenic Lynch syndrome 2016-10-14 criteria provided, single submitter clinical testing
Color RCV000583214 SCV000690414 pathogenic Hereditary cancer-predisposing syndrome 2020-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000657421 SCV000779156 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.3850dupA at the cDNA level and p.Thr1284AsnfsX5 (T1284NfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TATT[dupA]CGTT. The duplication causes a frameshift which changes a Threonine to an Asparagine at codon 1284, and creates a premature stop codon at position 5 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657421 SCV000889497 likely pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000501318 SCV000917748 likely pathogenic Lynch syndrome 2017-12-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3850dupA (p.Thr1284AsnfsX5) 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. One in silico tool predicts a damaging outcome for this variant. A variant that affects the same codon and leads to an equivalent change at the protein level (c.3847_3850dupATTA (p.Thr1284Asnfs)) as the variant of interest has been classified as pathogenic by multiple laboratories. Also, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3938_3941dupTTCA (p.Gln1314fsX6), c.3939_3957dupTCAAAAGGGACATAGAAAA (p.Ala1320fsX5), c.3939_3940dupTC (p.Gln1314fsX14)). This variant is absent in 276776 control chromosomes. In addition, one diagnostic laboratory 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.

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