ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3G>T (p.Met1Ile) (rs876660095)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219646 SCV000277232 pathogenic Hereditary cancer-predisposing syndrome 2018-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000485238 SCV000568008 likely pathogenic not provided 2016-10-18 criteria provided, single submitter clinical testing This variant alters the initiator Methionine codon, and the resultant protein would be described as “p.Met1?” to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. MSH6 c.3G>T has not been previously published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available information, we consider MSH6 c.3G>T to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680209 SCV000807674 likely pathogenic Lynch syndrome I 2016-11-03 reviewed by expert panel curation MSH6 initiation codon variant
Invitae RCV000793054 SCV000932389 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-09 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MSH6 mRNA. While this variant may disrupt protein translation of the MSH6 mRNA, an alternate in-frame methionine downstream of the original initiator codon located at codon 100 could potentially rescue translation initiation. However, experimental studies have not been performed to determine if an alternative initiator codon is utilized. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). Also, this variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual with features consistent with constitutional mismatch repair deficiency syndrome (PMID: 21520333). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 232954). 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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