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	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	2018-07-03	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 individuals affected with colorectal cancer (PMID: 28135145, 27978560, 15345113). ClinVar contains an entry for this variant (Variation ID: 89932). 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	RCV000570210	SCV000669547	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-01-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
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	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-30	criteria provided, single submitter	clinical testing