14-75018891-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting

The NM_001040108.2(MLH3):c.4180G>A(p.Ala1394Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1394A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.34

Publications

10 publications found

Variant links:

COSMIC-nc: COSV104587504

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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000191 (29/152150) while in subpopulation NFE AF = 0.000397 (27/68032). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.4180G>A	p.Ala1394Thr	missense_variant	Exon 12 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.4180G>A	p.Ala1394Thr	missense_variant	Exon 12 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251486

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000324

AC:

474

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

251

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000408

AC:

454

AN:

1112002

Other (OTH)

AF:

0.000215

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000191

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000272

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Aug 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A1394T variant (also known as c.4180G>A), located in coding exon 11 of the MLH3 gene, results from a G to A substitution at nucleotide position 4180. The alanine at codon 1394 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in individuals whose colon tumors demonstrated microsatellite stability and normal expression on immunohistochemistry (IHC) (Wu Y et al. Nat. Genet., 2001 Oct;29:137-8; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This alteration has also not been observed in a cohort of colorectal cancer patients (Hienonen T et al. Int. J. Cancer, 2003 Aug;106:292-6). Functional assays demonstrated similar MMR activity and expression for p.A1394T compared to wild-type MLH3 (Korhonen MK et al. Genes Chromosomes Cancer, 2008 Sep;47:803-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 7

Uncertain:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1394 of the MLH3 protein (p.Ala1394Thr). This variant is present in population databases (rs138006166, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 11586295, 19156873, 29212164). ClinVar contains an entry for this variant (Variation ID: 161297). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect MLH3 function (PMID: 18521850). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Colorectal cancer, non-polyposis

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;.;.;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;.

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.2

M;.;.;M

PhyloP100

7.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

D;.;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.90

MVP

0.92

MPC

0.50

ClinPred

0.65

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.66

gMVP

0.62

Mutation Taster

=27/73

disease causing

(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