ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1846_1848AAG[2] (p.Lys618del) (rs63751247)

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Total submissions: 16
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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 2015-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129328 SCV000186087 pathogenic Hereditary cancer-predisposing syndrome 2013-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000202279 SCV000211081 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MLH1 is denoted c.1852_1854delAAG at the cDNA level and p.Lys618del (K618del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAG[delAAG]GCTG. This variant, also published as MLH1 c.1852_1854del and K616del using alternate nomenclature, has been observed in multiple families with a phenotype consistent with Lynch syndrome (Hamilton 1995, Wijnen 1997, Wagner 2002, Hendriks 2003, Overbeek 2007, Arnold 2009, Bonadona 2011, Valentin 2011, Moreno-Ortiz 2016, Akbari 2017, Ricker 2017). Multiple functional studies have shown that this variant decreases MLH1 protein expression and reduces interaction with PMS2 and EXO1 (Guerrette 1999, Kondo 2003, Takahashi 2007). Additionally, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). MLH1 Lys618del was not observed in large population cohorts (Lek 2016). This deletion of a single Lysine residue is located in a region that interacts with PMS2, MLH3, PMS1, and EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Genetic Services Laboratory,University of Chicago RCV000192399 SCV000248052 pathogenic Lynch syndrome II 2014-12-05 criteria provided, single submitter clinical testing
Invitae RCV000524254 SCV000255268 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 16 of the MLH1 mRNA (c.1852_1854delAAG). This leads to the deletion of 1 amino acid residue in the MLH1 protein (p.Lys618del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals from several families affected with Lynch syndrome, and has been reported to segregate with disease (PMID: 10422993, 12891553). This variant is also known as del616 in the literature. ClinVar contains an entry for this variant (Variation ID: 17080). Multiple experimental studies have shown that this in-frame deletion causes a reduction in functional activity of the MLH1 protein (PMID: 10037723, 11427529, 12810663, 12891553, 17510385, 21120944). A multi-factorial likelihood analysis based on tumor characteristics and genetic and bioinformatics data also suggests that this variant is likely to be pathogenic (PMID: 22949379). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000192399 SCV000488529 pathogenic Lynch syndrome II 2016-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075383 SCV000592424 pathogenic Lynch syndrome 2014-04-22 criteria provided, single submitter clinical testing
Color RCV000129328 SCV000684776 pathogenic Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing
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: 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.
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000018609 SCV000038892 pathogenic Turcot syndrome 2017-12-11 no assertion criteria provided literature only
OMIM RCV000192399 SCV000038910 pathogenic Lynch syndrome II 2009-04-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202279 SCV000257069 pathogenic not provided no assertion criteria provided research
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093699 SCV001250883 likely pathogenic Lynch syndrome I 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

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