NM_000249.4:c.453+79A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000249.4(MLH1):c.453+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,213,338 control chromosomes in the GnomAD database, including 112,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.41 ( 13128 hom., cov: 32)

Exomes 𝑓: 0.43 ( 99539 hom. )

Consequence

MLH1
NM_000249.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: 0.347

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 3-37007142-A-G is Benign according to our data. Variant chr3-37007142-A-G is described in ClinVar as Benign. ClinVar VariationId is 90227.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 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	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.453+79A>G	intron	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.453+79A>G	intron	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.354+79A>G	intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.453+79A>G	intron	N/A	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.453+79A>G	intron	N/A	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.453+79A>G	intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61750

AN:

151922

Hom.:

13124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.535

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.411

Gnomad EAS

AF:

0.0777

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.458

Gnomad OTH

AF:

0.392

GnomAD4 exome

AF:

0.425

AC:

451544

AN:

1061298

Hom.:

99539

AF XY:

0.419

AC XY:

228559

AN XY:

545124

show subpopulations

African (AFR)

AF:

0.393

AC:

9746

AN:

24802

American (AMR)

AF:

0.374

AC:

15743

AN:

42060

Ashkenazi Jewish (ASJ)

AF:

0.426

AC:

10019

AN:

23540

East Asian (EAS)

AF:

0.118

AC:

4281

AN:

36420

South Asian (SAS)

AF:

0.262

AC:

20019

AN:

76532

European-Finnish (FIN)

AF:

0.371

AC:

18604

AN:

50156

Middle Eastern (MID)

AF:

0.374

AC:

1879

AN:

5024

European-Non Finnish (NFE)

AF:

0.466

AC:

352191

AN:

755956

Other (OTH)

AF:

0.407

AC:

19062

AN:

46808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

12784

25568

38351

51135

63919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8672

17344

26016

34688

43360

<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:

0.406

AC:

61772

AN:

152040

Hom.:

13128

Cov.:

AF XY:

0.399

AC XY:

29618

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.387

AC:

16049

AN:

41458

American (AMR)

AF:

0.413

AC:

6317

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

1426

AN:

3466

East Asian (EAS)

AF:

0.0777

AC:

402

AN:

5176

South Asian (SAS)

AF:

0.239

AC:

1153

AN:

4824

European-Finnish (FIN)

AF:

0.366

AC:

3860

AN:

10560

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.458

AC:

31158

AN:

67964

Other (OTH)

AF:

0.388

AC:

817

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1880

3760

5639

7519

9399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.418

Hom.:

4474

Bravo

AF:

0.408

Asia WGS

AF:

0.197

AC:

691

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Colorectal cancer, hereditary nonpolyposis, type 2 (1)

Lynch syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

7.3

(source)

DANN

Benign

0.81

PhyloP100

0.35

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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