3-37012077-A-G

Position:

chr3-37012077-A-G

Variant summary

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

The NM_000249.4(MLH1):c.655A>G(p.Ile219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,610,830 control chromosomes in the GnomAD database, including 71,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. I219L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.23 ( 4935 hom., cov: 32)

Exomes 𝑓: 0.29 ( 66306 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:27O:1

Conservation

PhyloP100: 2.05

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=0.0014769137).

BP6

Variant 3-37012077-A-G is Benign according to our data. Variant chr3-37012077-A-G is described in ClinVar as [Benign]. Clinvar id is 36557.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37012077-A-G is described in Lovd as [Benign]. Variant chr3-37012077-A-G is described in Lovd as [Likely_benign]. Variant chr3-37012077-A-G is described in Lovd as [Pathogenic]. Variant chr3-37012077-A-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.655A>G	p.Ile219Val	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.655A>G	p.Ile219Val	missense_variant	8/19	1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34464

AN:

152022

Hom.:

4934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0798

Gnomad AMI

AF:

0.426

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.0277

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.230

GnomAD3 exomes

AF:

0.233

AC:

58439

AN:

251064

Hom.:

8217

AF XY:

0.237

AC XY:

32113

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.0770

Gnomad AMR exome

AF:

0.165

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.0203

Gnomad SAS exome

AF:

0.135

Gnomad FIN exome

AF:

0.290

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.290

AC:

423077

AN:

1458690

Hom.:

66306

Cov.:

AF XY:

0.287

AC XY:

208258

AN XY:

725862

show subpopulations

Gnomad4 AFR exome

AF:

0.0757

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.292

Gnomad4 EAS exome

AF:

0.0374

Gnomad4 SAS exome

AF:

0.136

Gnomad4 FIN exome

AF:

0.295

Gnomad4 NFE exome

AF:

0.324

Gnomad4 OTH exome

AF:

0.262

GnomAD4 genome

AF:

0.226

AC:

34454

AN:

152140

Hom.:

4935

Cov.:

AF XY:

0.223

AC XY:

16558

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0795

Gnomad4 AMR

AF:

0.222

Gnomad4 ASJ

AF:

0.278

Gnomad4 EAS

AF:

0.0276

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.324

Gnomad4 OTH

AF:

0.228

Alfa

AF:

0.295

Hom.:

17788

Bravo

AF:

0.214

TwinsUK

AF:

0.324

AC:

1203

ALSPAC

AF:

0.327

AC:

1261

ESP6500AA

AF:

0.0921

AC:

406

ESP6500EA

AF:

0.320

AC:

2754

ExAC

AF:

0.232

AC:

28209

Asia WGS

AF:

0.0900

AC:

318

AN:

3478

EpiCase

AF:

0.323

EpiControl

AF:

0.324

ClinVar

Significance: Benign

Submissions summary: Benign:27Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2011	This variant is classified as benign based on its high frequency in the general population (rs1799977, MAF >3%). -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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)	Jun 24, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725) -

Lynch syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

Lynch syndrome 1

Benign:2

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -

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

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

0.00042

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.00014

P;P;P;P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.34

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.018

B;.

Vest4

0.057

MPC

0.075

ClinPred

0.0099

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.39

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