ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.628-2A>G (rs1114167725)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491365 SCV000580191 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000690593 SCV000818284 likely pathogenic Hereditary nonpolyposis colon cancer 2019-07-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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: 428338). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001010 SCV001158118 pathogenic not specified 2019-01-15 criteria provided, single submitter clinical testing The MSH6 c.628-2A>G variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 3, which is likely to disrupt gene function. Other truncating variants downstream of this variant have been identified in families with diagnosed or suspected Lynch syndrome and are considered pathogenic (Rossi 2017, Sjursen 2010). Based on available information, the c.628-2A>G variant is considered to be pathogenic. References: Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Sjursen W et al. Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. J Med Genet. 2010 Sep;47(9):579-85.

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