NM_000249.4:c.589-15C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.589-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,604,238 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 7 hom. )

Consequence

MLH1
NM_000249.4 intron

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:16

Conservation

PhyloP100: 0.321

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104573066

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]

MLH1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 3-37011996-C-T is Benign according to our data. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37011996-C-T is described in CliVar as Likely_benign. Clinvar id is 36556.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00544 (828/152234) while in subpopulation AFR AF = 0.0188 (782/41548). AF 95% confidence interval is 0.0177. There are 6 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.589-15C>T		intron_variant	Intron 7 of 18	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.589-15C>T		intron_variant	Intron 7 of 18	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00544

AC:

827

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00135

AC:

340

AN:

251328

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.0196

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000511

AC:

742

AN:

1452004

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

276

AN XY:

723062

show subpopulations

African (AFR)

AF:

0.0189

AC:

629

AN:

33270

American (AMR)

AF:

0.000581

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

1103010

Other (OTH)

AF:

0.00103

AC:

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00544

AC:

828

AN:

152234

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

361

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0188

AC:

782

AN:

41548

American (AMR)

AF:

0.00216

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00589

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nov 19, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:3

Nov 18, 2014

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. -

Feb 06, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 13, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1% in African population -

Apr 22, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Jul 12, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

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

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over