3-37012059-G-A

Position:

chr3-37012059-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.637G>A(p.Val213Met) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,613,896 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V213L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0076 ( 18 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 17 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:26O:1

Conservation

PhyloP100: 5.28

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009084314).

BP6

Variant 3-37012059-G-A is Benign according to our data. Variant chr3-37012059-G-A is described in ClinVar as [Benign]. Clinvar id is 41640.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37012059-G-A is described in Lovd as [Benign]. Variant chr3-37012059-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00758 (1154/152242) while in subpopulation AFR AF= 0.0264 (1097/41528). AF 95% confidence interval is 0.0251. There are 18 homozygotes in gnomad4. There are 549 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	8/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	8/19	1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00757

AC:

1151

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

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:

0.0000882

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00216

AC:

542

AN:

251170

Hom.:

AF XY:

0.00157

AC XY:

213

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000831

AC:

1214

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

512

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0272

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00758

AC:

1154

AN:

152242

Hom.:

Cov.:

AF XY:

0.00738

AC XY:

549

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0264

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.00852

ESP6500AA

AF:

0.0250

AC:

110

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:26Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:11Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.0% African chromosomes -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2014	- -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2014	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	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MLH1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 13, 2018	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 22, 2018	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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Lynch syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 08, 2015	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 28, 2021

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MLH1 p.Val213Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs2308317) as With Benign ,Uncertain significance allele , ClinVar (classified as benign by InSight, GenDx, Ambry Genetics, Invitae; classified as likely benign by Illumina), Clinvitae (classified as benign by ClinVar), UMD-LSDB (3X as neutral), Insight Colon Cancer Gene Variant Database (8X class 1), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 733(11 homozygous) of 276886 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 671 of 24030 chromosomes (freq: 0.028). Functional analysis of human MLH1 variants using yeast identify the variant has normal EXO1-binding, normal PMS2-binding and normal MMR function (Kondo 2003, Takahashi 2007). The variant functioned like the WT MLH1 in all of the assays in Raevaara (2005) with normal MMR function, normal nuclear concentration of MLH1 and normal nuclear concentration of the MLH1-PMS2 heterodimer. In addition, the variant has no effect on splicing in the pCAS ExVivo SplicingAssay (Tournier 2008) and concordant with patient RNA. The p.Val213 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Histidine kinase-like ATPase, ATP-binding domain DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.95

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.16

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.61

P;.

Vest4

0.54

MVP

0.77

MPC

0.098

ClinPred

0.017

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.55

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