NM_000249.4:c.2146G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.2146G>A(p.Val716Met) variant causes a missense change. The variant allele was found at a frequency of 0.00161 in 1,614,188 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:29O:1

Conservation

PhyloP100: 6.67

Variant links:

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07050222).

BP6

Variant 3-37050528-G-A is Benign according to our data. Variant chr3-37050528-G-A is described in ClinVar as [Benign]. Clinvar id is 41639.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050528-G-A is described in Lovd as [Likely_benign]. Variant chr3-37050528-G-A is described in Lovd as [Benign]. Variant chr3-37050528-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00136 (207/152352) while in subpopulation NFE AF= 0.00235 (160/68030). AF 95% confidence interval is 0.00205. There are 2 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.2146G>A	p.Val716Met	missense_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.2146G>A	p.Val716Met	missense_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00118

AC:

297

AN:

251090

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00163

AC:

2390

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1170

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.00189

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.00136

AC:

207

AN:

152352

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00104

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00235

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00122

AC:

148

EpiCase

AF:

0.00267

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:29Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 18, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2016

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jul 21, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 2013

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:7

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2019

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Oct 03, 2023

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

BA1 based on allele frequency in NFE of 0.00203 in gnomAD. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 02, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Oct 21, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Oct 03, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MLH1: BS3:Supporting, BS1, BS2 -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Jan 24, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2014

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. -

Jul 02, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lynch syndrome

Benign:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability <0.001 -

Breast and/or ovarian cancer

Benign:1

Dec 16, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;.;.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.071

T;T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

2.0

M;.;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;.;N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.15

T;.;D;D;D;D

Sift4G

Benign

0.15

T;D;D;D;D;T

Polyphen

0.97

D;.;.;.;.;.

Vest4

0.64

MVP

0.91

MPC

0.21

ClinPred

0.042

GERP RS

5.4

Varity_R

0.39

gMVP

0.70

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