ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3848_3850dup (p.Ile1283dup) (rs1553333420)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461225 SCV000551297 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-26 criteria provided, single submitter clinical testing This variant, c.3848_3850dupTTA, results in the insertion of 1 amino acid to the MSH6 protein (p.Ile1283dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760500213, ExAC 0.009%). This variant has been reported in individuals with suspected Lynch syndrome (PMID: 24689082, 27601186). ClinVar contains an entry for this variant (Variation ID: 410530). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485186 SCV000569625 uncertain significance not provided 2017-11-30 criteria provided, single submitter clinical testing This in-frame duplication of three nucleotides in MSH6 is denoted c.3848_3850dupTTA at the cDNA level and p.Ile1283dup (I1283dup) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ACTA[dupTTA]CGTT. This variant was observed in at least two individuals suspected of having Lynch syndrome (Lagerstedt-Robinson 2016), and was identified at similar frequencies between Icelandic colorectal cancer patients and controls (p=0.69) (Haraldsdottir 2017). This duplication of a single Isoleucine residue is located within the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Ile1283dup to be a variant of uncertain significance.
Ambry Genetics RCV000574392 SCV000662367 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000574392 SCV000685454 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing

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