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
Counsyl RCV000410339 SCV000489029 likely pathogenic Lynch syndrome II 2016-08-05 criteria provided, single submitter clinical testing
Invitae RCV000684811 SCV000543566 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 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.
Ambry Genetics RCV000568411 SCV000676057 pathogenic Hereditary cancer-predisposing syndrome 2019-12-09 criteria provided, single submitter clinical testing The c.454-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MLH1 gene. This mutation has been reported in a family that meets Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.

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