rs175080

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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:10

Conservation

PhyloP100: 1.89

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 257252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047125-G-A is described in Lovd as [Benign]. Variant chr14-75047125-G-A is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.2531C>T	p.Pro844Leu	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.2531C>T	p.Pro844Leu	missense_variant	2/13	5	NM_001040108.2	P1	Q9UHC1-1
MLH3	ENST00000380968.6 linkuse as main transcript	c.2531C>T	p.Pro844Leu	missense_variant	2/12	1			Q9UHC1-2
MLH3	ENST00000556257.5 linkuse as main transcript	c.2531C>T	p.Pro844Leu	missense_variant	2/7	5
MLH3	ENST00000555671.1 linkuse as main transcript	n.77C>T		non_coding_transcript_exon_variant	1/2	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

GnomAD3 exomes

AF:

0.404

AC:

101408

AN:

251230

Hom.:

22003

AF XY:

0.416

AC XY:

56468

AN XY:

135818

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 SAS exome

AF:

0.464

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

Gnomad4 AFR exome

AF:

0.401

Gnomad4 AMR exome

AF:

0.253

Gnomad4 ASJ exome

AF:

0.485

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.465

Gnomad4 FIN exome

AF:

0.456

Gnomad4 NFE exome

AF:

0.466

Gnomad4 OTH exome

AF:

0.444

GnomAD4 genome

AF:

0.423

AC:

64254

AN:

152064

Hom.:

13962

Cov.:

AF XY:

0.421

AC XY:

31281

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.353

Gnomad4 ASJ

AF:

0.486

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.463

Gnomad4 FIN

AF:

0.444

Gnomad4 NFE

AF:

0.461

Gnomad4 OTH

AF:

0.441

Alfa

AF:

0.448

Hom.:

24726

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2020	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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 19808033) -

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

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

MutationTaster

Benign

1.0

P;P;P;P;P

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

Varity_R

0.080

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over