Submissions for variant NM_000249.4(MLH1):c.52del (p.Arg18fs)

dbSNP: rs63749804

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075743	SCV000106750	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756339	SCV000884117	pathogenic	not provided	2017-12-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000756339	SCV001134314	pathogenic	not provided	2019-02-09	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Invitae	RCV001039846	SCV001203395	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-02-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in a family affected with colorectal cancer (PMID: 12132870). ClinVar contains an entry for this variant (Variation ID: 90254). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg18Alafs*18) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV002345380	SCV002644858	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-03	criteria provided, single submitter	clinical testing	The c.52delC pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 52, causing a translational frameshift with a predicted alternate stop codon (p.R18Afs*18). This mutation was identified in one Korean family with colorectal cancer (Kim JC et al. Cancer Detect. Prev. 2001;25:503-10). 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.	RCV003452743	SCV004187425	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.