rs17102999

Positions:

chr14-75046831-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040108.2(MLH3):c.2825C>T(p.Thr942Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,614,108 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 54 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 154 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.879

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=0.0017848909).

BP6

Variant 14-75046831-G-A is Benign according to our data. Variant chr14-75046831-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75046831-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.2825C>T	p.Thr942Ile	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.2825C>T	p.Thr942Ile	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020	P1	Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1584

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0495

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0128

AC:

3226

AN:

251340

Hom.:

AF XY:

0.0109

AC XY:

1484

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.0474

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.0534

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.00416

AC:

6082

AN:

1461772

Hom.:

154

Cov.:

AF XY:

0.00390

AC XY:

2837

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.0490

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.0550

Gnomad4 SAS exome

AF:

0.00272

Gnomad4 FIN exome

AF:

0.0134

Gnomad4 NFE exome

AF:

0.000326

Gnomad4 OTH exome

AF:

0.00583

GnomAD4 genome

AF:

0.0104

AC:

1583

AN:

152336

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

965

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.0654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0495

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00332

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00993

AC:

1206

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

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. -
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	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	This variant is associated with the following publications: (PMID: 16885347, 24759751, 20981092) -

MLH3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.11

T;.;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.78

T;T;T;.

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

L;L;.;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;.;T;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.085

B;P;.;B

Vest4

0.049

MPC

0.11

ClinPred

0.0067

GERP RS

1.7

Varity_R

0.037

gMVP

0.27

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