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
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680209 SCV000807674 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant in the initiation codon of MSH6
Ambry Genetics RCV000219646 SCV000277232 pathogenic Hereditary cancer-predisposing syndrome 2018-01-30 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.3G>T) is located in exon 1 of the MSH6 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000485238 SCV000568008 likely pathogenic not provided 2020-07-07 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (LaDuca 2017); This variant is associated with the following publications: (PMID: 28152038)
Invitae RCV000793054 SCV000932389 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-25 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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