Submissions for variant NM_000249.4(MLH1):c.1790G>A (p.Trp597Ter)

dbSNP: rs63750604

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075365	SCV000106359	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV003153348	SCV000543557	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp597*) 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 clinical features of Lynch syndrome (PMID: 21642682). ClinVar contains an entry for this variant (Variation ID: 89889). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000479277	SCV000569941	pathogenic	not provided	2016-04-08	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1790G>A at the cDNA level and p.Trp597Ter (W597X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Ambry Genetics	RCV000565193	SCV000676045	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	The p.W597* pathogenic mutation (also known as c.1790G>A), located in coding exon 16 of the MLH1 gene, results from a G to A substitution at nucleotide position 1790. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV003451068	SCV004186151	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492411	SCV004241743	pathogenic	Hereditary nonpolyposis colon cancer	2023-12-28	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1790G>A (p.Trp597X) results in a premature termination codon and is expected to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251290 control chromosomes (gnomAD). c.1790G>A has been reported in the literature in individuals affected with Gastric Cancer and Colorectal Cancer (e.g. Bacani_2005, Thompson_2013). A variant that leads to the same codon change was also reported in a HNPCC family (Bonadona_2011). These data indicate that the variant is very likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21642682, 22949379, 16237216). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000565193	SCV004359251	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with gastric cancer with clinical features of MLH1-associated Lynch syndrome (PMID: 16237216). 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	RCV000479277	SCV000778616	pathogenic	not provided	2017-11-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354093	SCV001548622	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Trp597* variant was identified in 2 of 746 proband chromosomes (frequency: 0.003) from individuals or families with colon or gastric cancer (Bacani 2005, Thompson 2013). The variant was also identified in dbSNP (ID: rs63750604 as "With Pathogenic allele"), ClinVar (5x as pathogenic by InSiGHT, Invitae, GeneDx, Ambry Genetics, and Mayo Clinic Genetic Testing Laboratories), Mismatch Repair Genes Variant Database, and InSiGHT Hereditary Tumors database. The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The MLH1 c.1790G>A variant leads to a premature stop codon at position 597, which is predicted to lead to a truncated protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.