3-37047639-AA-GC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2PM5BP6_Very_Strong

The NM_000249.4(MLH1):​c.1852_1853delAAinsGC​(p.Lys618Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

MLH1
NM_000249.4 missense

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:4B:24O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37047639-AA-ATTCTT is described in Lovd as [Pathogenic].
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 rank MANE Protein UniProt
MLH1NM_000249.4 linkc.1852_1853delAAinsGC p.Lys618Ala missense_variant ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.1852_1853delAAinsGC p.Lys618Ala missense_variant 1 NM_000249.4 ENSP00000231790.3 P40692-1

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:24Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:7Other:1
Jan 13, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Nov 29, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:2
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2010
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Jul 13, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 06, 2024
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Jan 25, 2016
Vantari Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Feb 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MLH1: BS1, BS2 -

Nov 06, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Lynch syndrome Benign:2
Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: research

Multifactorial likelihood analysis posterior probability <0.001 -

Sep 23, 2020
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Jun 22, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1
Nov 10, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1
Jul 24, 2014
Pathway Genomics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Muir-Torré syndrome Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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