Submissions for variant NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)

dbSNP: rs63751247

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075383	SCV000106376	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Abrogated function (reduced expression in 2 independent assays), >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000129328	SCV000184091	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The c.1852_1854delAAG pathogenic mutation (also known as p.K618del), located in coding exon 16 of the MLH1 gene, results from an in-frame AAG deletion at nucleotide positions 1852 to 1854 causing the in-frame deletion of a highly conserved lysine at codon 618. In one yeast study, this mutation (designated as 1846-48del) exhibited 38.9% in vitro MMR activity and less than 25% of MLH1 protein expression when compared to wild-type (Takahashi M et al. Cancer Res. 2007 May;67:4595-604). In another study analyzing the dimerization of MLH1 and PMS2 proteins it was noted that the lysine at codon 618, when mutated, led to nearly undetectable interaction levels with PMS2 when compared to wild-type (Guerrette S et al. J. Biol. Chem. 1999 Mar;274:6336-41). This mutation has been reported in multiple families with HNPCC/Lynch syndrome and/or Lynch syndrome associated cancers (Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Takahashi M et al. Cancer Res. 2007 May;67:4595-604; South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81; Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). This alteration has also been detected by our laboratory in multiple individuals diagnosed with an early-onset MLH1-associated cancer whose tumors demonstrated absent MLH1 and PMS2 staining on immunohistochemistry (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Ambry Genetics	RCV000129328	SCV000186087	pathogenic	Hereditary cancer-predisposing syndrome	2013-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000202279	SCV000211081	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased MLH1 protein expression, reduced MMR activity relative to wildtype, and reduced interaction with PMS2 and EXO1 (Guerrette 1999, Kondo 2003, Takahashi 2007); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27435373, 27247567, 25980754, 28449805, 30376427, 8581513, 9697702, 10037723, 12810663, 16083711, 17510385, 17594722, 20591884, 21120944, 22949379, 24362816, 25117503, 7661930, 18726168, 15996210, 21681552, 25430799, 26777316, 28176205, 23047549, 26681312, 28127413, 28874130, 28640387, 17846840, 28135145, 29520894, 30693488, 12891553, 29929473, 29478780, 10422993, 30402230, 18566915, 29345684, 31350202, 9311737, 31332305, 33504652)
Genetic Services Laboratory, University of Chicago	RCV000192399	SCV000248052	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2014-12-05	criteria provided, single submitter	clinical testing
Invitae	RCV000524254	SCV000255268	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-20	criteria provided, single submitter	clinical testing	This variant, c.1852_1854del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Lys618del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782285, gnomAD 0.0009%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 12891553). It has also been observed to segregate with disease in related individuals. This variant is also known as del616. ClinVar contains an entry for this variant (Variation ID: 17080). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Experimental studies have shown that this variant affects MLH1 function (PMID: 10037723, 11427529, 12810663, 12891553, 17510385, 21120944). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000192399	SCV000488529	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129328	SCV000684776	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	clinical testing	This variant is a 1 amino acid deletion located in exon 16 of the MLH1 protein. The variant is also known as del616 in the literature. Multiple experimental functional studies have shown that this variant significantly abrogates MLH1 protein function by reducing MLH1 protein expression or stability, and reducing interaction with PMS2 and EXO1 (PMID: 10037723, 11427529, 12810663, 12891553, 16083711, 17510385, 18373977, 21120944, 29520894, 9697702). This variant has been reported in numerous individuals affected with Lynch Syndrome cancers (PMID: 10422993, 10480359, 12414824, 12547705, 12891553, 12891553, 14635101, 17453009, 18566915, 19267393, 19419416, 25280751, 28176205, 28640387, 29520894, 31491536, 7661930, 8581513, 8993976, 8993976, 9311737). It has also been shown to segregate with disease in Lynch Syndrome families (PMID: 12891553, 8993976). This variant has been identified in 1/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202279	SCV000885706	pathogenic	not provided	2018-04-11	criteria provided, single submitter	clinical testing	The MLH1 c.1852_1854delAAG; p.Lys618del variant (rs63751247), also known as Lys616del, is a common alteration in individuals diagnosed with Lynch syndrome, and segregates with the disorder (Miyaki 1995, Raevaara 2003, LOVD InSiGHT database). Functional characterization of the variant protein indicates reduced mismatch repair activity due to decreased steady state levels of MLH1 protein (Raevaara 2005, Shimodaira 1998, Takehashi 2007) and reduced localization with PMS2 and EXO1 (Kondo 2003, Raevaara 2005). It is classified as pathogenic in ClinVar (Variation ID: 17080) by the International Society for Gastrointestinal Hereditary Tumours (Thompson 2014). Based on available information, this variant is considered pathogenic. REFERENCES LOVD InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?select_db=MLH1 Kondo E et al. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003; 63(12):3302-8. Miyaki M et al. Germ line mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. J Mol Med (Berl). 1995; 73(10):515-20. Raevaara T et al. Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein. Gastroenterology. 2003; 125(2):501-9. Raevaara T et al. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology. 2005; 129(2):537-49. Shimodaira H et al. Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. Nat Genet. 1998; 19(4):384-9. Takahashi M et al. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007; 67(10):4595-604. Thompson B et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014; 46(2):107-15.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075383	SCV000917668	pathogenic	Lynch syndrome	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1852_1854delAAG (p.Lys618del) results in an in-frame deletion that is predicted to remove one Lys amino acid from the C-terminal domain (IPR032189) of the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 246244 control chromosomes (gnomAD). c.1852_1854delAAG has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Viel 1997, Wang 1999, Farrington 1998, Raevaara 2005, Ricker 2017, Koger 2018). In many of these cases the tumor tissue was shown to be MLH1/PMS2 negative by IHC, and microsatellite instable (e.g. Ricker 2017, Koger 2018). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, demonstrating reduced expression and MMR activity (e.g. Takahashi 2007, Koger 2018). Multi-factorial likelihood analysis also suggested a pathogenic role for the variant (Thompson 2013, Thompson 2014). Four 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202279	SCV001450056	pathogenic	not provided	2019-06-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202279	SCV001469800	pathogenic	not provided	2019-12-28	criteria provided, single submitter	clinical testing	This variant has been reported in individuals affected with colorectal, endometrial, ovarian, bladder, and prostate cancers and Lynch Syndrome in the published literature (PMIDs: 30521064 (2019), 29929473 (2018), 28176205 (2017), 25117503 (2014), 23047549 (2012), and 20591884 (2010)). In addition, studies indicate that this variant has deleterious effects on MLH1 protein expression in yeast and human cell based functional studies (PMIDs: 29520894 (2018), 16083711 (2005), and 12891553 (2003)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000202279	SCV002017491	pathogenic	not provided	2020-06-29	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000192399	SCV002102409	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-11-18	criteria provided, single submitter	research	A heterozygous 3 base pair deletion in exon 16 of the MLH1 gene (Depth: 275x) that results in the in-frame deletion of amino acid, Lysine at codon 618 (p.Lys618del) was detected. This in-frame deletion reduces the functional activity of the MLH1 protein and is documented as pathogenic in hereditary nonpolyposis colon cancer in the ClinVar database. The p.Lys618del variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by MutationTaster2 tool. The reference region is conserved across species.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202279	SCV002550855	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV001093699	SCV002573624	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490387	SCV002780667	pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000192399	SCV004193023	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-02-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000075383	SCV004843223	pathogenic	Lynch syndrome	2023-12-10	criteria provided, single submitter	clinical testing	This variant is a 1 amino acid deletion located in exon 16 of the MLH1 protein. The variant is also known as del616 in the literature. Multiple experimental functional studies have shown that this variant significantly abrogates MLH1 protein function by reducing MLH1 protein expression or stability, and reducing interaction with PMS2 and EXO1 (PMID: 10037723, 11427529, 12810663, 12891553, 16083711, 17510385, 18373977, 21120944, 29520894, 9697702). This variant has been reported in numerous individuals affected with Lynch Syndrome cancers (PMID: 10422993, 10480359, 12414824, 12547705, 12891553, 12891553, 14635101, 17453009, 18566915, 19267393, 19419416, 25280751, 28176205, 28640387, 29520894, 31491536, 7661930, 8581513, 8993976, 8993976, 9311737). It has also been shown to segregate with disease in Lynch Syndrome families (PMID: 12891553, 8993976). This variant has been identified in 1/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000018609	SCV000038892	pathogenic	Mismatch repair cancer syndrome 1	2017-12-11	no assertion criteria provided	literature only
OMIM	RCV000192399	SCV000038910	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2009-04-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202279	SCV000257069	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353903	SCV000592424	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Lys618del variant was identified in 14 of 3448 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome (Nilbert 2009, Overbeek 2007, Raevaara 2005). The variant was also identified in dbSNP (ID: rs121912962) “With pathogenic allele”, HGMD, UMD (117X as a causal variant), “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and the COSMIC database, and the ClinVar database where it was classified as a pathogenic variant by two submitters (OMIM and InSiGHT). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 618, within the 3-lysine region including codons 616–618. Shimodaira (1998) notes that this variant co-segregates with disease, and tumours with the variant have shown high microsatellite instability and loss of MLH1 by immunohistochemistry staining (Raevaara 2005, Overbeek 2007). Functional assays have demonstrated a deleterious effect of the variant, including reduced MLH1 expression, reduced protein interactions with ExoI and/or PMS2, abnormal nuclear localization, reduced mismatch repair activity, and loss or reduction of the dominant mutator effect as compared to wild type MLH1 (Raevaara 2005, Schmutte 2001 Shimodaira 1998, Takahashi 2007). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093699	SCV001250883	likely pathogenic	Lynch syndrome 1		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249999	SCV001423900	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202279	SCV001744362	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202279	SCV001967790	pathogenic	not provided		no assertion criteria provided	clinical testing