Submissions for variant NM_000249.4(MLH1):c.1554dup (p.Glu519Ter)

dbSNP: rs63751689

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075242	SCV000106236	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000813027	SCV000953360	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu519*) 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 premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 7812952, 11112663, 21520333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89768).
Ambry Genetics	RCV001012097	SCV001172511	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-29	criteria provided, single submitter	clinical testing	The c.1554dupT pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a duplication of T at nucleotide position 1554. This changes the amino acid from a glutamate to a stop codon (p.E519*). This alteration has been described in multiple families with Lynch Syndrome (Kolodner RD et al. Cancer Res. 1995 Jan;55(2):242-8; Scott RJ et al. Am. J. Hum. Genet. 2001 Jan;68(1):118-127). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321497	SCV004026157	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_SUP, PS3
Genetics and Molecular Pathology, SA Pathology	RCV003447487	SCV004175289	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-08	criteria provided, single submitter	clinical testing	The MLH1 c.1554dup variant is classified as Pathogenic (PVS1, PM2, PP1) This MLH1 c.1554dup variant is located in exon 13/19 and is predicted to result in premature termination of the protein product at codon 519. This is predicted to result in the loss of protein function and nonsense mediated decay (NMD) is a known mechanism of disease (PMID: 20860725) (PVS1). This variant is absent from population databases (PM2). This variant was found to co-segregate with disease in multiple members of a single family (PMID: 7812952) (PP1). The variant has been reported in dbSNP (rs63751689) and in the HGMD database (CI951952). It has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 89768).
Myriad Genetics, Inc.	RCV003447487	SCV004186461	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 termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003447487	SCV004190665	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-27	criteria provided, single submitter	clinical testing