NM_001040108.2:c.2531C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040108.2(MLH3):c.2531C>T(p.Pro844Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,336 control chromosomes in the GnomAD database, including 164,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P844S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.42 ( 13962 hom., cov: 33)

Exomes 𝑓: 0.45 ( 150649 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.89

Publications

105 publications found

Variant links:

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

MLH3 Gene-Disease associations (from GenCC):

colorectal cancer, hereditary nonpolyposis, type 7
Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

MLH3 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 (MetaRNN=4.402101E-4).

BP6

Variant 14-75047125-G-A is Benign according to our data. Variant chr14-75047125-G-A is described in ClinVar as Benign. ClinVar VariationId is 257252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.2531C>T	p.Pro844Leu	missense_variant	Exon 2 of 13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MLH3	ENST00000355774.7 link	c.2531C>T	p.Pro844Leu	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6 link	c.2531C>T	p.Pro844Leu	missense_variant	Exon 2 of 12	1		ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000556257.5 link	c.2531C>T	p.Pro844Leu	missense_variant	Exon 2 of 7	5		ENSP00000451540.1	G3V419
MLH3	ENST00000555671.1 link	n.77C>T		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.423

AC:

64203

AN:

151946

Hom.:

13947

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.486

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.463

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.461

Gnomad OTH

AF:

0.434

GnomAD2 exomes

AF:

0.404

AC:

101408

AN:

251230

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.400

Gnomad AMR exome

AF:

0.240

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.454

Gnomad NFE exome

AF:

0.460

Gnomad OTH exome

AF:

0.435

GnomAD4 exome

AF:

0.449

AC:

655716

AN:

1461272

Hom.:

150649

Cov.:

AF XY:

0.450

AC XY:

327339

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.401

AC:

13418

AN:

33472

American (AMR)

AF:

0.253

AC:

11336

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

12684

AN:

26128

East Asian (EAS)

AF:

0.161

AC:

6408

AN:

39684

South Asian (SAS)

AF:

0.465

AC:

40072

AN:

86252

European-Finnish (FIN)

AF:

0.456

AC:

24358

AN:

53412

Middle Eastern (MID)

AF:

0.490

AC:

2828

AN:

5766

European-Non Finnish (NFE)

AF:

0.466

AC:

517786

AN:

1111462

Other (OTH)

AF:

0.444

AC:

26826

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

23220

46439

69659

92878

116098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15298

30596

45894

61192

76490

<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:

0.423

AC:

64254

AN:

152064

Hom.:

13962

Cov.:

AF XY:

0.421

AC XY:

31281

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.400

AC:

16573

AN:

41474

American (AMR)

AF:

0.353

AC:

5395

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.486

AC:

1687

AN:

3470

East Asian (EAS)

AF:

0.152

AC:

787

AN:

5170

South Asian (SAS)

AF:

0.463

AC:

2232

AN:

4820

European-Finnish (FIN)

AF:

0.444

AC:

4699

AN:

10572

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.461

AC:

31355

AN:

67958

Other (OTH)

AF:

0.441

AC:

933

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1939

3878

5817

7756

9695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.442

Hom.:

34037

Bravo

AF:

0.411

TwinsUK

AF:

0.473

AC:

1755

ALSPAC

AF:

0.455

AC:

1754

ESP6500AA

AF:

0.403

AC:

1776

ESP6500EA

AF:

0.463

AC:

3981

ExAC

AF:

0.412

AC:

50076

Asia WGS

AF:

0.364

AC:

1265

AN:

3478

EpiCase

AF:

0.459

EpiControl

AF:

0.457

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2020

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. -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

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

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19808033) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 25, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP6 -

Endometrial carcinoma

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.12

T;.;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.65

T;T;T;.

MetaRNN

Benign

0.00044

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

L;L;.;L

PhyloP100

1.9

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Benign

0.11

Sift

Benign

0.29

T;.;T;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

0.0010

B;B;.;B

Vest4

0.076

MPC

0.10

ClinPred

0.0085

GERP RS

4.1

PromoterAI

-0.0074

Neutral

(source)

Varity_R

0.080

gMVP

0.22

Mutation Taster

=298/2

polymorphism (auto)

(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