3-37047631-TGAA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_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 (★★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MLH1
NM_000249.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:28

Conservation

PhyloP100: 9.08
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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 Protein UniProt
MLH1NM_000249.4 linkuse as main transcriptc.1852_1854del p.Lys618del inframe_deletion 16/19 ENST00000231790.8 NP_000240.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.1852_1854del p.Lys618del inframe_deletion 16/191 NM_000249.4 ENSP00000231790 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251422
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461870
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:28
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:9
Pathogenic, no assertion criteria providedresearchMayo Clinic Laboratories, Mayo Clinic-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 28, 2019This 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, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJun 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 29, 2020- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 21, 2020Published 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, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 11, 2018The 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. -
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 05, 2014- -
Pathogenic, criteria provided, single submitterclinical testingCounsylApr 20, 2016- -
Pathogenic, criteria provided, single submitterresearchFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsNov 18, 2021A 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 submitterclinical testingBaylor GeneticsFeb 12, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del LiliAug 16, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 2009- -
Lynch syndrome Pathogenic:3
Pathogenic, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013Abrogated 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 -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 26, 2018Variant 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 submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 10, 2023This 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. -
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 20, 2022The 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 submitterclinical testingAmbry GeneticsJan 22, 2013- -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 06, 2021This 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 submitterclinical testingUniversity of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)-- -
Likely pathogenic, no assertion criteria providedclinical testingDing PR Lab, Sun Yat-sen University Cancer Center-- -
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 22, 2022- -
Lynch-like syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingConstitutional Genetics Lab, Leon Berard Cancer CenterJul 01, 2019- -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2024This 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 providedliterature onlyOMIMDec 11, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs63751247; hg19: chr3-37089122; API