Submissions for variant NM_000249.4(MLH1):c.76C>T (p.Gln26Ter)

dbSNP: rs63749827

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075838	SCV000106852	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000520796	SCV000616776	pathogenic	not provided	2017-04-12	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.76C>T at the cDNA level and p.Gln26Ter (Q26X) at the protein level.The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), andis predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported in several individuals with Lynch syndrome (Katballe 2002, Bonadona 2011,Toon 2013, Walsh 2010, Serrano 2012) and is considered pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258082	SCV001434924	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-01-17	criteria provided, single submitter	clinical testing	This c.76C>T (p.Gln26*) variant in the MLH1 gene was predicted to result in a premature stop codon and has not been reported in general population databases. This variant has been reported in multiple unrelated patients with colorectal cancer (PMID 10419591, 11772966, 20215533, 22776989, 23197718) or endometrial cancer (PMID 20215533). Micro satellite instability or MLH1 loss were observed in some of the tumors (PMID 11772966, 20215533). Therefore, the c.76C>T (p.Gln26*) variant in the MLH1 gene was classified as pathogenic.
Invitae	RCV001854309	SCV002232838	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-05-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 22776989, 20215533). ClinVar contains an entry for this variant (Variation ID: 90347). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) 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).
Ambry Genetics	RCV002399450	SCV002673213	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.Q26* pathogenic mutation (also known as c.76C>T) located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 76. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been reported in multiple individuals with Lynch syndrome tumors (Walsh MD, Clin Cancer Res. 2010 Apr; 16(7):2214-24; Nilbert M et al. Fam. Cancer 2009 Jun;8(1):75-83; Toon CW et al. Am. J. Surg. Pathol. 2013 Oct;37(10):1592-602; Katballe N et al. Gut 2002 Jan;50(1):43-51). In addition, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Hum. Mutat. 2013 Jan;34(1):200-9). 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.
Myriad Genetics, Inc.	RCV001258082	SCV004186407	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000520796	SCV001958746	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000520796	SCV001968374	pathogenic	not provided		no assertion criteria provided	clinical testing