Submissions for variant NM_000249.4(MLH1):c.1489del (p.Arg497fs)

dbSNP: rs63750855

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075226	SCV000106218	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557252	SCV000625072	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-06-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg497Glyfs*11) 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 present in population databases (rs763560251, gnomAD 0.003%). 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: 89752). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001011841	SCV001172214	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-30	criteria provided, single submitter	clinical testing	The c.1489delC pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.R497Gfs*11). This mutation was identified in a patient with colorectal cancer at 46 and Muir-Torre phenotype (Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60; South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a patient with endometrial cancer showing absent MLH1 and PMS2 protein expression by immunohistochemistry (Moline J et al. Gynecol. Oncol. 2013 Jul;130:121-6). 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315404	SCV004015209	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing	MLH1 (Arg497fs): This sequence change creates a premature translational stop signal (p.Arg497Glyfs*11) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with Lynch syndrome and Muir-Torre syndrome (PMID: 15872200, 18270343). ClinVar contains an entry for this variant (Variation ID: 89752) with 3 submissions, all pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). Therefore, this variant has been classified as Pathogenic. .
Myriad Genetics, Inc.	RCV003315404	SCV004186557	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.