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 2021-03-29 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of the critical regions of interaction with EXO1, PMS2/MLH3/PMS1 (Plotz 2003, Kosinski 2010, Andersen 2012); Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in individuals with colon cancer (Rajkumar 2004, Pearlman 2017, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 27978560, 15345113, 22753075, 20533529, 12799449, 30720243)
Invitae RCV000524638 SCV000625106 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-07-07 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 been observed in individual(s) with colorectal cancer (PMID: 28135145, 27978560, 15345113). This variant is also known as IVS16-2A>G in the literature. 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 The c.1897-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 17 in the MLH1 gene. This alteration has been identified in two probands with early-onset colorectal cancer, one of whom had a MSI-high tumor and met Bethesda criteria for Lynch syndrome; however, the colon tumor of the second proband was reported to be mismatch repair (MMR) proficient demonstrating microsatellite stability and/or normal immunohistochemistry (Rajkumar T et al. Genet. Test. 2004 ;8(2):157-62; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). This variant was also reported in an individual from a cohort of unselected colorectal cancer patients undergoing multigene panel testing (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration does not result in significant abnormal splicing compared to non-carrier control samples (Ambry internal data). Of note, this alteration is also designated as IVS16-2A>G in the published literature. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000570210 SCV000908649 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-15 criteria provided, single submitter clinical testing

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