Submissions for variant NM_000249.4(MLH1):c.1624C>T (p.Gln542Ter)

dbSNP: rs63750192

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075283	SCV000106276	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001201351	SCV000253787	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln542*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15024732, 22480969). ClinVar contains an entry for this variant (Variation ID: 89809). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657575	SCV000779312	pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1624C>T at the cDNA level and p.Gln542Ter (Q542X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals with hereditary non-polyposis colorectal cancer (HNPCC), one of whom had a tumor that showed microsatellite instability (MSI-H) and lack of MLH1 protein expression by immunohistochemistry (Tournier 2004, Bonnet 2012). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657575	SCV001134294	pathogenic	not provided	2019-01-04	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV002399438	SCV002704281	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-06	criteria provided, single submitter	clinical testing	The p.Q542* pathogenic mutation (also known as c.1624C>T), located in coding exon 14 of the MLH1 gene, results from a C to T substitution at nucleotide position 1624. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This pathogenic mutation has been reported in several families diagnosed with HNPCC/Lynch syndrome (Tournier I et al. Hum Mutat. 2004 Apr;23(4):379-84; Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10). This alteration has also been reported in a family with Turcot syndrome where the proband was diagnosed with colon cancer at age 44 and with a glioblastoma at age 62. The glioblastoma showed a loss of MLH1 on IHC (Lebrun C et al. Eur J Neurol. 2007 Apr;14(4):470-2). 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.
Myriad Genetics, Inc.	RCV003451042	SCV004186382	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657575	SCV004243146	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing