Submissions for variant NM_000249.4(MLH1):c.2035G>T (p.Glu679Ter)

dbSNP: rs587778971

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075489	SCV000106485	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507295	SCV000601382	likely pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529563	SCV000625117	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu679*) 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 variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 90005). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001014093	SCV001174763	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The p.E679* variant (also known as c.2035G>T), located in coding exon 18 of the MLH1 gene, results from a G to T substitution at nucleotide position 2035. This changes the amino acid from a glutamic acid to a stop codon within coding exon 18. This mutation was seen along with MLH1 copy-neutral loss of heterozygosity (CN-LOH) in an MSI-H colorectal tumor demonstrating loss of MLH1 and PMS2 by IHC (Gray PN et al. Oncotarget, 2018 Apr;9:20304-20322). 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.	RCV003451095	SCV004188670	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353532	SCV000592435	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Glu679* variant has only been sequenced once by our laboratory. It is predicted to cause a nonsense mutation, which alters the protein's amino acid sequence leading to a premature stop codon at codon 679. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of Lynch syndrome for the MLH1 gene. In summary, based on the above information, this variant is classified as pathogenic.