Submissions for variant NM_000249.4(MLH1):c.2142G>A (p.Trp714Ter)

dbSNP: rs63750978

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481539	SCV000565170	pathogenic	not provided	2019-10-30	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 43 amino acids are lost, and other loss-of-function variants have been reported downstream in Clinvar (Landrum 2014); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21901500, 8880570, 11093816, 27601186, 9833759, 25345868, 19931546, 15322516, 17510385, 9697702, 28514183, 28466842, 29238914, 25110875, 31447099)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588239	SCV000696148	pathogenic	Lynch syndrome	2016-09-23	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.2142G>A (p.Trp714X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2179_2182delCACA (p.His727fsX55) and c.2252_2253delAA (p.Lys751fsX3). Multiple publications cite the variant in affected individuals, along with a reputable database classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae	RCV000817498	SCV000958062	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp714*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the MLH1 protein. 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: 8880570). This variant is also known as 2163G>A. ClinVar contains an entry for this variant (Variation ID: 418308). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys732*) have been determined to be pathogenic (PMID: 10422993, 10923051, 12799449, 16338176, 20533529, 25197397; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000481539	SCV002024360	pathogenic	not provided	2019-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431389	SCV002731156	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	The p.W714* pathogenic mutation (also known as c.2142G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2142. 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 6% 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 seen in an English HNPCC family containing multiple family members with colorectal cancer (Froggatt NJ et al. J. Med. Genet. 1996 Sep;33:726-30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003449165	SCV004186317	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	RCV003449165	SCV004193035	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-09-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481539	SCV004220873	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been observed in individuals with Lynch syndrome or a Lynch Syndrome associated phenotype (PMID: 8880570 (1996), PMID: 31447099 (2019), PMID: 29238914 (2018), PMID: 21901500 (2012), PMID: 15731775 (2005)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002431389	SCV004359274	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	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. Although functional studies have not been reported, this variant is expected to disrupt the PMS2/MLH3/PMS1 interacting domain (PMID: 12799449, 16338176, 20533529). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8880570, 25345868; DOI: 10.3343/lmo.2018.8.4.156; Salehi 2008). 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.
GeneReviews	RCV001805097	SCV002054055	not provided	Lynch syndrome 1		no assertion provided	literature only