Submissions for variant NM_000249.4(MLH1):c.1783_1784del (p.Ser595fs)

dbSNP: rs63750035

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075364	SCV000106358	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000684798	SCV000543636	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser595Trpfs*14) 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: 8571956, 12810663, 15849733, 20459533). ClinVar contains an entry for this variant (Variation ID: 89888). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001013138	SCV001173682	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The c.1783_1784delAG pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 1783 to 1784, causing a translational frameshift with a predicted alternate stop codon (p.S595Wfs*14). This mutation has been identified in multiple families who met either Bethesda guidelines or Amsterdam diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). In a yeast-based assay, MLH1 protein with this mutation demonstrated decreased interaction with PMS2 compared to wild-type (Kondo E et al. Cancer Res. 2003 Jun 15;63(12):3302-8). 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	RCV002307389	SCV002600603	pathogenic	Hereditary nonpolyposis colon cancer	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1783_1784delAG (p.Ser595TrpfsX14) 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 251268 control chromosomes (gnomAD). c.1783_1784delAG has been reported in the literature in multiple affected individuals and at least one family meeting Amsterdam criteria for Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome (e.g. Wijnen_1996, Genuardi_1998, Mangold_2005, Barrow_2010). These data indicate that the variant is very likely to be associated with disease. An experimental study using a yeast two-hybrid model system to evaluate the impact of the variant on protein function found that it severely impaired the ability of MLH1 to interact with PMS2 compared to the wild-type protein (e.g. Kondo_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002460909	SCV002756555	pathogenic	not provided	2022-05-20	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; Identified in individuals with personal or family history of Lynch-associated cancers, including those whose tumors demonstrated loss of MLH1 expression and/or microsatellite instability (Wijnen 1996, Mangold 2005, Yang 2021); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Published functional studies demonstrate defective DNA binding and decreased interaction with PMS2 (Kondo 2003); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 593594 del 2bp; This variant is associated with the following publications: (PMID: 10601588, 8571956, 16216036, 12810663, 34178123)
Myriad Genetics, Inc.	RCV000018638	SCV004190028	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.
OMIM	RCV000018637	SCV000038920	pathogenic	Mismatch repair cancer syndrome 1	2007-06-01	no assertion criteria provided	literature only
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250015	SCV001423916	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
OMIM	RCV000018638	SCV002601715	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2007-06-01	no assertion criteria provided	literature only