ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3762_3763delinsTT (p.Glu1254_Asp1255delinsAspTyr) (rs878853738)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232565 SCV000283821 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-13 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 8 of the MSH6 mRNA (c.3762_3763delAGinsTT), leading to the substitution of 2 amino acid residues in the MSH6 protein (p.Glu1254_Asp1255delinsAspTyr) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 237197). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids 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 RCV000478739 SCV000565235 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3762_3763delAGinsTT at the cDNA level and p.Glu1254_Asp1255delinsAspTyr (E1254_D1255delinsDY) at the protein level. The surrounding sequence is TAGA[delAG][insTT]ATTA. The deletion and insertion results in the replacement of a Glutamic Acid and an Aspartic Acid residue with an Aspartic Acid and a Tyrosine residue, creating two adjacent missense changes: Glu1254Asp and Asp1255Tyr. This combined variant has not, to our knowledge, been reported in the literature as a pathogenic or benign germline variant. MSH6 c.3762_3763delAGinsTT was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 c.3762_3763delAGinsTT is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564937 SCV000669967 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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