rs28756990

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.2221G>T(p.Val741Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,926 control chromosomes in the GnomAD database, including 235 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V741I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 68 hom., cov: 33)

Exomes 𝑓: 0.011 ( 167 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:11

Conservation

PhyloP100: -0.895

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=0.0023878515).

BP6

Variant 14-75047435-C-A is Benign according to our data. Variant chr14-75047435-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 5561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047435-C-A is described in Lovd as [Pathogenic]. Variant chr14-75047435-C-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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.2221G>T	p.Val741Phe	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.2221G>T	p.Val741Phe	missense_variant	2/13	5	NM_001040108.2	P1	Q9UHC1-1
MLH3	ENST00000380968.6 linkuse as main transcript	c.2221G>T	p.Val741Phe	missense_variant	2/12	1			Q9UHC1-2
MLH3	ENST00000556257.5 linkuse as main transcript	c.2221G>T	p.Val741Phe	missense_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3128

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0504

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0418

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0134

AC:

3378

AN:

251380

Hom.:

AF XY:

0.0142

AC XY:

1931

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0478

Gnomad AMR exome

AF:

0.00729

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0122

Gnomad SAS exome

AF:

0.0375

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00741

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0109

AC:

15960

AN:

1461726

Hom.:

167

Cov.:

AF XY:

0.0115

AC XY:

8396

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0523

Gnomad4 AMR exome

AF:

0.00762

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0101

Gnomad4 SAS exome

AF:

0.0361

Gnomad4 FIN exome

AF:

0.00156

Gnomad4 NFE exome

AF:

0.00835

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.0206

AC:

3134

AN:

152200

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1512

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0504

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.0419

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.00794

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00920

Hom.:

Bravo

AF:

0.0215

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.0520

AC:

229

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.0145

AC:

1762

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2022	The c.2221G>T (p.Val741Phe) variant in MLH3 is classified as benign since it has ben identified in 5% of African chromosomes in gnomAD, including 35 homozygotes. ACMG/AMP Criteria_ BA1. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 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. -

Colorectal cancer, hereditary nonpolyposis, type 7

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MLH3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Endometrial carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.0

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;.;.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.82

T;T;T;.

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.034

D;.;D;D

Sift4G

Uncertain

0.045

D;D;T;D

Polyphen

0.89

P;P;.;P

Vest4

0.12

MPC

0.40

ClinPred

0.037

GERP RS

-6.3

Varity_R

0.044

gMVP

0.31

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