rs587782285
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000249.4(MLH1):c.1852_1854del(p.Lys618del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L615L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MLH1
NM_000249.4 inframe_deletion
NM_000249.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.08
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000249.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000249.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 3-37047631-TGAA-T is Pathogenic according to our data. Variant chr3-37047631-TGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 17080.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047631-TGAA-T is described in Lovd as [Pathogenic]. Variant chr3-37047631-TGAA-T is described in Lovd as [Likely_pathogenic]. Variant chr3-37047631-TGAA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.1852_1854del | p.Lys618del | inframe_deletion | 16/19 | ENST00000231790.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.1852_1854del | p.Lys618del | inframe_deletion | 16/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251422Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461870Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:27
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:9
| Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 29, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 28, 2019 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2020 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 11, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 11, 2019 | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:5
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2014 | - - |
| Pathogenic, criteria provided, single submitter | research | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Nov 18, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 20, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2023 | - - |
Lynch syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 26, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 10, 2023 | 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. - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | 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 - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2021 | 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. - |
Lynch syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Ding PR Lab, Sun Yat-sen University Cancer Center | - | - - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 22, 2022 | - - |
Lynch-like syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | 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. - |
Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 11, 2017 | - - |
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