Submissions for variant NM_000249.4(MLH1):c.142C>T (p.Gln48Ter)

dbSNP: rs587778913

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075212	SCV000106204	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000219426	SCV000279805	pathogenic	not provided	2016-01-20	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.142C>T at the cDNA level and p.Gln48Ter (Q48X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature as either a pathogenic germline variant or a benign polymorphism, it is considered pathogenic.
Invitae	RCV001214512	SCV001386196	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-05-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89738). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln48*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219426	SCV001469791	pathogenic	not provided	2020-04-03	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 patient with expected phenotype for this gene, and not found in general population data.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000219426	SCV002009374	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390218	SCV002701036	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.Q48* pathogenic mutation (also known as c.142C>T), located in coding exon 2 of the MLH1 gene, results from a C to T substitution at nucleotide position 142. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV003451027	SCV004189841	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	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.
CZECANCA consortium	RCV001270940	SCV001451744	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing