Genetic Variant MLH1:p.Ile219Val (chr3-37012077-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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:31O:1

Conservation

PhyloP100: 2.05

Publications

254 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 36 uncertain in NM_000249.4

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 VariationId is 36557.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.655A>G	p.Ile219Val	missense	Exon 8 of 19	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.655A>G	p.Ile219Val	missense	Exon 8 of 18	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.556A>G	p.Ile186Val	missense	Exon 7 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.655A>G	p.Ile219Val	missense	Exon 8 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.655A>G	p.Ile219Val	missense	Exon 8 of 17	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.655A>G	p.Ile219Val	missense	Exon 8 of 15	ENSP00000416476.2	H0Y806

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

GnomAD2 exomes

AF:

0.233

AC:

58439

AN:

251064

AF XY:

0.237

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 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

African (AFR)

AF:

0.0757

AC:

2531

AN:

33454

American (AMR)

AF:

0.171

AC:

7669

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7613

AN:

26104

East Asian (EAS)

AF:

0.0374

AC:

1485

AN:

39690

South Asian (SAS)

AF:

0.136

AC:

11689

AN:

86226

European-Finnish (FIN)

AF:

0.295

AC:

15773

AN:

53408

Middle Eastern (MID)

AF:

0.260

AC:

1499

AN:

5758

European-Non Finnish (NFE)

AF:

0.324

AC:

359002

AN:

1109010

Other (OTH)

AF:

0.262

AC:

15816

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

14039

28079

42118

56158

70197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11276

22552

33828

45104

56380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34454

AN:

152140

Hom.:

4935

Cov.:

AF XY:

0.223

AC XY:

16558

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0795

AC:

3304

AN:

41542

American (AMR)

AF:

0.222

AC:

3385

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

965

AN:

3468

East Asian (EAS)

AF:

0.0276

AC:

143

AN:

5178

South Asian (SAS)

AF:

0.126

AC:

609

AN:

4832

European-Finnish (FIN)

AF:

0.289

AC:

3055

AN:

10568

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22052

AN:

67960

Other (OTH)

AF:

0.228

AC:

481

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1265

2531

3796

5062

6327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.289

Hom.:

30277

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Colorectal cancer, hereditary nonpolyposis, type 2 (5)

not provided (5)

Lynch syndrome (4)

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome 1 (2)

Hereditary nonpolyposis colorectal neoplasms (1)

Malignant tumor of breast (1)

Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.21

Eigen_PC

Benign

0.00042

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

2.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.29

Sift

Benign

0.34

Sift4G

Benign

0.50

Polyphen

0.018

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

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over