Submissions for variant NM_000249.4(MLH1):c.117-1G>T

dbSNP: rs587779950

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000680196	SCV000807660	likely pathogenic	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Variant at IVS±1
Ambry Genetics	RCV002331313	SCV002633302	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	The c.117-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 2 of the MLH1 gene. This mutation, designated as 117-1G>K in published literature, has been detected in Spanish and Brazilian Lynch syndrome families (Martin Ruiz JL et al. Int J Colorectal Dis. 2013 Oct;28(10):1451-2; Rossi BM et al. BMC Cancer. 2017 Sep 5;17(1):623). RNA and minigene assays have demonstrated that this mutation causes aberrant splicing (Ruiz JL et al. Int J Colorectal Dis. 2014 Aug;29(8):1019-20). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.