Submissions for variant NM_000249.4(MLH1):c.2135G>A (p.Trp712Ter)

dbSNP: rs63750561

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075550	SCV000106547	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon with functional domain
Color Diagnostics, LLC DBA Color Health	RCV000581002	SCV000684800	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the MLH1 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Functional assays have demonstrated the variant impacts PMS2 interaction (PMID: 12810663). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8574961, 11720433, 20233461, 27329137). 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.
Invitae	RCV000686456	SCV000813975	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp712*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the MLH1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*) have been determined to be pathogenic (PMID: 10422993, 16338176, 20533529). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90065). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8574961, 12624141, 12810663, 15855432, 20233461). This variant is not present in population databases (gnomAD no frequency).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310200	SCV001499801	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000202047	SCV001772661	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and the published literature (Kondo 2003, Mohd 2006, Kosinski 2010, Stenson 2014); Published functional studies demonstrate a damaging effect: variant impairs PMS2 and EXO1 binding (Kondo 2003); Observed in individuals with HNPCC-associated cancers (Liu 1996, Coleman 2001, Kondo 2003, Pigatto 2004); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27978560, 26666765, 15555211, 20233461, 15855432, 12624141, 10422993, 16338176, 20533529, 12810663, 8574961, 11720433)
Revvity Omics, Revvity	RCV000202047	SCV002017493	pathogenic	not provided	2019-05-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581002	SCV002731079	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	The p.W712* pathogenic mutation (also known as c.2135G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2135. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 46 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MLH1-related disease (Ambry internal data). This pathogenic mutation has been reported in multiple families with HNPCC/Lynch syndrome where the proband's tumor showed microsatellite instability (Liu B et al. Nat. Med. 1996 Feb;2:169-74; Coleman MG et al. Br. J. Cancer. 2001 Nov;85:1486-91). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451108	SCV004190065	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	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.
Baylor Genetics	RCV003451108	SCV004193075	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-06-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000075550	SCV004843282	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the MLH1 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Functional assays have demonstrated the variant impacts PMS2 interaction (PMID: 12810663). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8574961, 11720433, 20233461, 27329137). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202047	SCV000257087	pathogenic	not provided		no assertion criteria provided	research