Submissions for variant NM_000249.4(MLH1):c.37G>T (p.Glu13Ter)

dbSNP: rs587779008

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075677	SCV000106680	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000162469	SCV000212832	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	The p.E13* pathogenic mutation (also known as c.37G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 37. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This pathogenic mutation has been reported in a multiple individuals with suspicion for Lynch syndrome (Brzia D et al. Exp. Oncol. 2012;34(1):49-52; Rouleau E et al. Hum. Mutat. 2009 Jun;30(6):867-75; Ikenoue T et al. J Hum Genet, 2019 Dec;64:1187-1194; Henriksson I et al. J Community Genet, 2019 Apr;10:259-266). This pathogenic mutation has also been identified in several probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MLH1 and/or PMS2 expression by immunohistochemistry (Ambry internal data; Pearlman R et al. J Med Genet, 2019 07;56:462-470). 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.
Invitae	RCV000696247	SCV000824799	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90189). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 22453149, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu13*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).
Myriad Genetics, Inc.	RCV003451138	SCV004186480	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.