Submissions for variant NM_000249.4(MLH1):c.67del (p.Glu23fs)

dbSNP: rs63750822

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075823	SCV000106833	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000575040	SCV000673815	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The c.67delG pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 67, causing a translational frameshift with a predicted alternate stop codon (p.E23Kfs*13). This alteration was identified once in a Danish Lynch syndrome cohort (Nilbert M et al. Fam. Cancer, 2009 Jun;8:75-83). 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.
Invitae	RCV000817865	SCV000958448	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu23Lysfs*13) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90332). This variant is also known as c.63del and c.66delG. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15342696, 15713769, 16451135, 18566915, 19224586, 25081409). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193211	SCV001361917	pathogenic	Hereditary nonpolyposis colon cancer	2019-09-05	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.67delG (p.Glu23LysfsX13) 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. The variant was absent in 251404 control chromosomes (gnomAD). c.67delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (LS) or LS related cancers (e.g. Domingo _2004, Ferguson_2014, Dymerska_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001353400	SCV002522532	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PVS1
Myriad Genetics, Inc.	RCV003452762	SCV004190059	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353400	SCV000592329	uncertain significance	not provided		no assertion criteria provided	clinical testing