Submissions for variant NM_000249.4(MLH1):c.1758dup (p.Met587fs)

dbSNP: rs63749863

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075355	SCV000106349	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000573311	SCV000676035	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The c.1758dupC pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a duplication of C at nucleotide position 1758, causing a translational frameshift with a predicted alternate stop codon (p.M587Hfs*6). This variant was reported in multiple Korean individuals with features consistent with Lynch syndrome (Han et al. Hum. Mol. Genet. 1995; 4(2)237-42; Shin et al. Hum. Mutat. 2004;24(4):351; Wei et al. J. Bioinform. Comput. Biol. 2010; 8(Suppl. 1):111-25; Shin et al. Obstet Gynecol. Sci. 2015; 58(2):112-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230396	SCV003928875	pathogenic	Hereditary nonpolyposis colon cancer	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1758dupC (p.Met587HisfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251270 control chromosomes (gnomAD). c.1758dupC has been reported in the literature in individuals affected with Lynch Syndrome, and was shown to segregate with disease in an affected family (e.g. Kim_2009). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating that while the N-terminal portion of the MLH1 protein was detectable, the C-terminal portion was undetectable in patient derived colon tissue samples (Kim_2009), in addition the truncated protein was unable to bind to Pms2 in a yeast two-hybrid assay (Kondo_2003). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003451064	SCV004190039	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003451064	SCV004193042	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-07-19	criteria provided, single submitter	clinical testing
Invitae	RCV003593879	SCV004293467	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89879). This variant is also known as 586 ins 1bp . This premature translational stop signal has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 7757073). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met587Hisfs*6) 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).
GeneReviews	RCV001804816	SCV002054064	not provided	Lynch syndrome 1		no assertion provided	literature only