Submissions for variant NM_000249.4(MLH1):c.901C>T (p.Gln301Ter)

dbSNP: rs63750489

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075928	SCV000106944	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001223223	SCV001395362	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln301*) 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 Lynch syndrome (PMID: 8993976, 14871975, 18307539, 20305446, 26517685). ClinVar contains an entry for this variant (Variation ID: 90435). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287363	SCV002578088	pathogenic	See cases	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP4,PP5
Ambry Genetics	RCV002371912	SCV002683511	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	clinical testing	The p.Q301* pathogenic mutation (also known as c.901C>T), located in coding exon 11 of the MLH1 gene, results from a C to T substitution at nucleotide position 901. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been detected in multiple families with HNPCC/Lynch syndrome (Viel A et al. Genes Chromosomes Cancer. 1997 Jan;18:8-18; de Jong AE et al. Clin. Cancer Res. 2004 Feb;10:972-80; Naseem H et al. Clin. Genet. 2006 Nov;70:388-95; Ponz de Leon M et al. Br. J. Cancer. 2004 Feb;90:882-7; Yan HL et al. Cancer Sci. 2008 Apr;99:770-80; Jóri B et al. Oncotarget, 2015 Dec;6:41108-22; Chubb D et al. Nat Commun, 2016 06;7:11883; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; ). 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.	RCV003452788	SCV004190067	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	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.
Color Diagnostics, LLC DBA Color Health	RCV002371912	SCV004359211	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 8993976, 18307539, 20305446) or suspect Lynch syndrome (PMID: 14871975), and an individual with endometrial cancer that exhibited loss of MLH1 protein by immunohistochemistry analyses (PMID: 26517685). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701489	SCV001932997	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701489	SCV001967939	pathogenic	not provided		no assertion criteria provided	clinical testing