Submissions for variant NM_000249.4(MLH1):c.1772_1775del (p.Asp591fs)

dbSNP: rs63749868

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075362	SCV000106356	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000202011	SCV000568567	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MLH1-related cancers (PMID: 26248088, 29228462); This variant is associated with the following publications: (PMID: 26248088, 8872463, 12810663, 29228462, 17312306)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202011	SCV000601367	pathogenic	not provided	2016-07-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572736	SCV000676015	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	The c.1772_1775delATAG pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 1772 to 1775, causing a translational frameshift with a predicted alternate stop codon (p.D591Vfs*24). This mutation has been previously identified in multiple unrelated individuals, whose personal and family history either met Amsterdam I/II criteria or Bethesda guidelines for testing for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Lagerstedt Robinson K et al. J Natl Cancer Inst. 2007 Feb 21; 99(4): 291-9; Moslein G et al. Hum. Mol. Genet. 1996 Sep;5:1245-52; Guindalini RS et al. Gastroenterology. 2015 Nov;149:1446-53). 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.
Color Diagnostics, LLC DBA Color Health	RCV000572736	SCV000689839	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-14	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 16 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome, colorectal, or endometrial cancer (PMID: 8872463, 17312306, 26248088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV000694036	SCV000822461	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp591Valfs*24) 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 colorectal cancer and Lynch syndrome (PMID: 8872463, 12810663, 17312306, 26248088). This variant is also known as 590–591 del TAGA. ClinVar contains an entry for this variant (Variation ID: 89886). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199947	SCV001370745	pathogenic	Hereditary nonpolyposis colon cancer	2020-05-29	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1772_1775delATAG (p.Asp591ValfsX24) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. c.1772_1775delATAG has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example, Moslein_1996, Lagerstedt Robinson_2007, Guindalini_2015). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000202011	SCV001446920	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407452	SCV004109707	pathogenic	MLH1-related disorder	2023-06-08	criteria provided, single submitter	clinical testing	The MLH1 c.1772_1775delATAG variant is predicted to result in a frameshift and premature protein termination (p.Asp591Valfs*24). This variant, also referred to as 590-591 delTAGA, has been reported to be pathogenic for colorectal cancer (Moslein et al 1996. PubMed ID: 8872463; Kondo E et al 2003. PubMed ID: 12810663; Table S1 Guindalini RS et al 2015. PubMed ID: 26248088). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MLH1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV003451066	SCV004186319	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	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	RCV003451066	SCV004190648	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202011	SCV000257064	pathogenic	not provided		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250014	SCV001423915	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing