14-75017109-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001040108.2(MLH3):c.4335A>G(p.Gln1445Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,612,868 control chromosomes in the GnomAD database, including 236,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21708 hom., cov: 33)

Exomes 𝑓: 0.54 ( 214606 hom. )

Consequence

MLH3
NM_001040108.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.637

Publications

55 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.004).

BP6

Variant 14-75017109-T-C is Benign according to our data. Variant chr14-75017109-T-C is described in ClinVar as Benign. ClinVar VariationId is 257253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.637 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.4335A>G	p.Gln1445Gln	synonymous_variant	Exon 13 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 link	c.4335A>G	p.Gln1445Gln	synonymous_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79996

AN:

152034

Hom.:

21692

Cov.:

show subpopulations

Gnomad AFR

AF:

0.442

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.627

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.836

Gnomad SAS

AF:

0.495

Gnomad FIN

AF:

0.554

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.523

GnomAD2 exomes

AF:

0.575

AC:

144593

AN:

251482

AF XY:

0.564

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.749

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.833

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.532

Gnomad OTH exome

AF:

0.549

GnomAD4 exome

AF:

0.537

AC:

784611

AN:

1460716

Hom.:

214606

Cov.:

AF XY:

0.535

AC XY:

389080

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.433

AC:

14492

AN:

33450

American (AMR)

AF:

0.734

AC:

32839

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

13352

AN:

26104

East Asian (EAS)

AF:

0.828

AC:

32849

AN:

39686

South Asian (SAS)

AF:

0.498

AC:

42979

AN:

86238

European-Finnish (FIN)

AF:

0.542

AC:

28945

AN:

53362

Middle Eastern (MID)

AF:

0.484

AC:

2789

AN:

5766

European-Non Finnish (NFE)

AF:

0.526

AC:

584025

AN:

1111046

Other (OTH)

AF:

0.536

AC:

32341

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

19768

39537

59305

79074

98842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16824

33648

50472

67296

84120

<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:

0.526

AC:

80052

AN:

152152

Hom.:

21708

Cov.:

AF XY:

0.529

AC XY:

39380

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.443

AC:

18378

AN:

41532

American (AMR)

AF:

0.627

AC:

9589

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1768

AN:

3468

East Asian (EAS)

AF:

0.837

AC:

4333

AN:

5178

South Asian (SAS)

AF:

0.495

AC:

2389

AN:

4824

European-Finnish (FIN)

AF:

0.554

AC:

5862

AN:

10580

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.530

AC:

36049

AN:

67972

Other (OTH)

AF:

0.516

AC:

1090

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1957

3913

5870

7826

9783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.529

Hom.:

32691

Bravo

AF:

0.532

Asia WGS

AF:

0.603

AC:

2099

AN:

3478

EpiCase

AF:

0.532

EpiControl

AF:

0.535

ClinVar

Significance: Benign

Submissions summary: Benign:11

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

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

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 30, 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

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.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.2

(source)

DANN

Benign

0.59

PhyloP100

-0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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