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

Total submissions: 8

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