Submissions for variant NM_000249.4(MLH1):c.2141G>A (p.Trp714Ter)

dbSNP: rs63751022

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075553	SCV000106549	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon with functional domain
Ambry Genetics	RCV000165669	SCV000216407	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	clinical testing	The p.W714* pathogenic mutation (also known as c.2141G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2141. 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 43 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 reported in numerous families with Lynch syndrome (Hutter P et al. J. Med. Genet. 1996 Aug;33(8):636-40; Sheng JQ et al. Chin. J. Dig. Dis. 2006;7(4):197-205; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Takahashi M et al. Cancer Res. 2007 May;67(10):4595-604; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075553	SCV000696149	pathogenic	Lynch syndrome	2016-07-06	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.2141G>A (p.Trp714X) variant results in a premature termination codon, predicted to cause a truncation of C-terminal domain, a known mechanisms for disease. The functional studies demonstrated that hMLH1-hMRE11 interaction was dramatically decreased by p.Trp714X, and truncated protein lacks MMR activity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2179_2182delCACA/p.His727fsX55). This variant has been reported in numerous Lynch Syndrome patients and is absent in 121240 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV001044497	SCV001208298	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-31	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). 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*, 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. Experimental studies have shown that this premature translational stop signal affects MLH1 function (PMID: 9697702, 12810663, 17510385). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90068). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8863153, 30256826). It has also been observed to segregate with disease in related individuals.
Color Diagnostics, LLC DBA Color Health	RCV000165669	SCV001735270	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes defective PMS2 interaction (PMID: 12810663) and loss of mismatch repair activity (PMID: 9697702, 17510385). This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 21642682, 23640085, 27601186, 30256826). This variant has been shown to segregate with disease in a large Lynch syndrome family (PMID: 8863153). 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.
GeneDx	RCV002280100	SCV002568555	pathogenic	not provided	2022-08-26	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 the Human Gene Mutation Database (HGMD); Observed in several unrelated patients from different ethnic backgrounds with Lynch-related cancers in published literature, some of which showing tumor studies consistent with pathogenic variants in this gene (Froggatt 1996, Kondo 2003, Sheng 2006, Bonadona 2011, Martin-Morales 2018); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: inability to induce dominant mutator effect, loss of mismatch repair activity, and decreased protein expression (Shimodaira 1998, Takahashi 2007); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); This variant is associated with the following publications: (PMID: 8863153, 25504677, 12810663, 30256826, 19931546, 25345868, 27601186, 15322516, 11093816, 8880570, 28514183, 17510385, 9697702, 17054581, 21642682, 23640085, 31830689, 9833759)
Myriad Genetics, Inc.	RCV003451110	SCV004189899	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075553	SCV004848353	pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The p.Trp714X variant in MLH1 has been reported in 4 individuals with Lynch syndrome and segregated with disease in 7 affected individuals from one family (Hutter 1996, Fu 2013, Lagerstedt-Robinson 2016, Martin-Morales 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 90068). This nonsense variant leads to a premature termination codon at position 714. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that this variant does impact protein function (Takahashi 2007). This variant was classified as Pathogenic on Sep 05, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID SCV000106549.2).In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PM4, PP1_Strong, PS3_Supporting.
Pathway Genomics	RCV000144606	SCV000189933	pathogenic	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing