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rs35502531

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP6_Very_Strong

The NM_000249.4(MLH1):c.1852_1853delinsGC(p.Lys618Ala) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618IL?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

MLH1
NM_000249.4 missense

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:4B:20O:1

Conservation

PhyloP100: 7.33
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000249.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37047640-A-TTCTT is described in ClinVar as [Pathogenic]. Clinvar id is 89908.Status of the report is reviewed_by_expert_panel, 3 stars.
BP6
Variant 3-37047639-AA-GC is Benign according to our data. Variant chr3-37047639-AA-GC is described in ClinVar as [Benign]. Clinvar id is 17089.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.1852_1853delinsGC p.Lys618Ala missense_variant 16/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.1852_1853delinsGC p.Lys618Ala missense_variant 16/191 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Benign
Submissions summary: Uncertain:4Benign:20Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:5Other:1
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedresearchMayo Clinic Laboratories, Mayo Clinic-- -
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 31, 2021- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 29, 2021- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 13, 2017- -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:2
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Likely benign, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Uncertain significance, no assertion criteria providedliterature onlyOMIMAug 01, 2010- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 13, 2015- -
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsJan 03, 2018- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 16, 2021This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitterclinical testingVantari GeneticsJan 25, 2016- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024MLH1: BS1, BS2 -
Benign, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Lynch syndrome Benign:2
Benign, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013Multifactorial likelihood analysis posterior probability <0.001 -
Benign, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalSep 23, 2020- -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 22, 2023- -
Carcinoma of colon Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Lys618Ala variant has been previously reported in the literature. It has been identified in 48/8212 (Freq: 0.006) proband chromosomes from families with colorectal cancer and or other cancer types and in 29/6204 (Freq: 0.005) control chromosomes, increasing the likelihood that this is a polymorphism (Auclair_2006_16395668; Barnetson_2008_18033691; Belvederesi_2006_16724012; Bianchi_2007_17250665; Fearnhead_2004_15520370; Fidalgo_2000_10713887; Gille_2002_12373605; Hampel_2006_16885385; Hedge_2005_16237223; Hudler_2004_15099349; Papp_2007_17569143; Perera_2007_18205192; Pinol_2005_15855432; Rubio-Del-Campo_2007_18325052; Scott_2001_11112663; Steinke_2008_18301448; Syngal_1999_10422993; Ward_2002_12200596; Weber_1997_9288790; Wolf_200515926618; Wijnen_1997_9311737; Tannergard_1995_8521398). Contradictory evidence exists regarding the functional significance of this variant. In vitro studies have demonstrated that the p.Lys618Ala substitution results in an 85% reduction in efficiency of binding to PMS2 and that it was unable to reverse the mutator phenotype in an MLH1 deficient ovarian cancer cell line (Blasi_2006_16982745; Guerrette_1999_10037723). However, Perera et al (2007) demonstrated that the p.Lys618Ala variant did not appear to perturb the ability of MLH1 to heterodimerize with the PMS2 protein. Although, they also showed that the variant protein had a half-life that was significantly decreased compared to the wild-type protein (Perera_2007_18205192), suggesting that this variant may have some functional consequence. There is a significant evidence against the pathogenicity of this variant. Previous studies have identified p.Lys618Ala variant in patients with Microsatelite Stable colorectal carcinomas that expressed MLH1 (Farrington et al., 1998; Liu_1999_10598809; Mauillon et al., 1996; Muller-Koch_2001_11726306; Samowitz et al., 2001; Wolf_2005_15926618). Several studies report this variant in the presence of a second variant which was in some cases pathogenic. For example an out-of-frame splice mutation (a A>G at position –2 in intron 6 of the hMLH1-gene). The splice mutation caused skipping of exon 7 and was shared with a younger sibling who had three consecutive CRCs and gastric cancer, all associated with MSI (Liu_1999_10598809). In this case, the p.Lys618Ala variant did not co-segregate with disease (Tannergard_1995_8521398). Still in another study, the MSH2 protein product was demonstrated to be absent and the MLH1 protein product was present in one affected individual with this variant, increasing the likelihood that the p.Lys618Ala variant is not pathogenic (Pinol_2005_15855432). Steinke et al (2008_18301448) also identified this variant in the presence of a second variant in two individuals, one was a pathogenic stop codon (Syngal_1999_10422993). In summary, based on the above information, this variant is predicted to be benign. Although it is predicted benign we cannot rule out that it may contribute to or modify the clinical features observed in this individual. -
Lynch syndrome 1 Benign:1
Likely benign, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 10, 2021- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs35502531; hg19: chr3-37089130; COSMIC: COSV104573019; API