ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1897-2A>G (rs267607871)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075411 SCV000106407 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
GeneDx RCV000487325 SCV000565163 likely pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1897-2A>G or IVS16-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 16 of the MLH1 gene. The 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 at least three individuals with colorectal cancer, one of whom had a tumor displaying microsatellite instability (Rajkumar 2004, Pearlman 2017, Yurgelun 2017). We consider this variant to be likely pathogenic.
Invitae RCV000524638 SCV000625106 likely pathogenic Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 16 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 not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 89932). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: 5713769, 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 RCV000570210 SCV000669547 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing Insufficient evidence;RNA Studies
Integrated Genetics/Laboratory Corporation of America RCV000075411 SCV000696134 likely pathogenic Lynch syndrome 2016-05-24 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1897-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/3 splice prediction tools predict loss of canonical splicing acceptor site. ESEfinder predicts loss of binding motifs for RNA splicing enhancers. This variant was absent in 121378 control chromosomes, and has been shown to co-segregate with colon cancer in one family (RAJKUMAR_MLH1&MSH2_Genetic Testing_2004). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
Counsyl RCV000662785 SCV000785594 likely pathogenic Lynch syndrome II 2017-09-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763104 SCV000893646 likely pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000570210 SCV000908649 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-15 criteria provided, single submitter clinical testing

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