Submissions for variant NM_000249.4(MLH1):c.1644C>G (p.Tyr548Ter)

dbSNP: rs63751087

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075289	SCV000106282	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV002399440	SCV002709248	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	clinical testing	The p.Y548* pathogenic mutation (also known as c.1644C>G), located in coding exon 14 of the MLH1 gene, results from a C to G substitution at nucleotide position 1644. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been detected in two colorectal patients meeting Amsterdam criteria for HNPCC/Lynch syndrome, with one patient's tumor demonstrating high microsatellite instability (MSI-high) and loss of MLH1/PMS2 staining on immunohistochemistry (IHC) (Hajer J et al. Hum Mutat, 2000 Aug;16:181; Buchanan DD et al. J Gastroenterol Hepatol, 2017 Feb;32:427-438). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.