Submissions for variant NM_000179.2(MSH6):c.3802-7_3802-4del (rs876661171)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219815	SCV000279708	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3802-7_3802-4delTCTT or IVS8-7_IVS8-4delTCTT and consists of a deletion of four nucleotides at the -4 through -7 positions in intron 8 of the MSH6 gene. The normal sequence with the bases that are deleted in brackets is tctt[deltctt]aagG, where the capital letters are exonic and lowercase are intronic. Using alternate nomenclature, this variant may be defined as c.3802-13_3802-10delTTTC. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016).This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. Based on the currently available information, we consider MSH6 c.3802-7_3802-4delTCTT to be a variant of uncertain significance.
Ambry Genetics	RCV000491776	SCV000580092	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-03-16	criteria provided, single submitter	clinical testing	Insufficient evidence;RNA Studies;Other data supporting pathogenic classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Color	RCV000491776	SCV000904155	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000801331	SCV000941105	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-11-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome-associated cancers (PMID: 21520333, external communication). It has also been observed to segregate with Lynch syndrome-associated cancers in a family (external communication). ClinVar contains an entry for this variant (Variation ID: 234703). Experimental studies have shown that this variant disrupts mRNA splicing (external communication). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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