ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.454-1G>C (rs193922370)

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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 RCV000568411 SCV000676057 pathogenic Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Other strong data supporting pathogenic classification
Counsyl RCV000410339 SCV000489029 likely pathogenic Lynch syndrome II 2016-08-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000472090 SCV000696167 likely pathogenic Lynch syndrome 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.454-1G>C variant affects a conserved intronic nucleotide at the invariant AG acceptor splice site of intron 5. Mutation Taster predicts damaging outcome for this variant, and 4/5 Alamut algorithms predict elimination of the splice acceptor site; however, the variant has not been evaluated for functional impact by in vivo/vitro studies. This variant was not found in 120912 control chromosomes, but has been cited in 1 HNPCC family (Wagner_AJHG_2003); and a similar variant, c.454-1G>A, has been cited in HNPCC patients from multiple families and has been classified as pathogenic. Additionally, frameshift, splice-site, and nonsense variants downstream of this variant have been classified as pathogenic (i.e. p.Arg487X, p.Asp591fsX24, c.1731G>A, etc). Taken together, this variant was classified as likely pathogenic until additional information is available.
Invitae RCV000684811 SCV000543566 likely pathogenic Hereditary nonpolyposis colon cancer 2018-06-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MLH1 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 been observed in an individual affected with Lynch syndrome (PMID: 12658575). This variant is also known as IVS5-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 371909). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 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.

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