ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.381-1G>A (rs267607744)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205947 SCV000259785 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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). Variants that disrupt this acceptor splice site have been observed in several individuals affected with Lynch syndrome, and have been reported to segregate with disease in a family (PMID: 26248088, 28944238, 8971183, Invitae). ClinVar contains an entry for this variant (Variation ID: 219740). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000480828 SCV000565144 pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.381-1G>A or IVS4-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 4 of the MLH1 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in association with Lynch syndrome (Guindalini 2015, Roth 2016). Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480828 SCV000601397 likely pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV001021211 SCV001182794 pathogenic Hereditary cancer-predisposing syndrome 2019-09-04 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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