rs41562513

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1558+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,872 control chromosomes in the GnomAD database, including 1,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.053 ( 289 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1151 hom. )

Consequence

MLH1
NM_000249.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:24

Conservation

PhyloP100: -0.851

Publications

16 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=-0.82).

BP6

Variant 3-37028946-G-A is Benign according to our data. Variant chr3-37028946-G-A is described in ClinVar as Benign. ClinVar VariationId is 36541.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0967 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.1558+14G>A	intron	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.1558+14G>A	intron	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.1459+14G>A	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.1558+14G>A	intron	N/A	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.1558+14G>A	intron	N/A	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.1558+14G>A	intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

AF:

0.0533

AC:

8104

AN:

152074

Hom.:

287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0989

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0334

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.0187

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0387

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0392

Gnomad OTH

AF:

0.0502

GnomAD2 exomes

AF:

0.0366

AC:

9200

AN:

251280

AF XY:

0.0355

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.0357

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0368

AC:

53820

AN:

1461678

Hom.:

1151

Cov.:

AF XY:

0.0361

AC XY:

26230

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.101

AC:

3396

AN:

33474

American (AMR)

AF:

0.0213

AC:

953

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0252

AC:

659

AN:

26136

East Asian (EAS)

AF:

0.0181

AC:

718

AN:

39696

South Asian (SAS)

AF:

0.0189

AC:

1626

AN:

86254

European-Finnish (FIN)

AF:

0.0357

AC:

1903

AN:

53374

Middle Eastern (MID)

AF:

0.0397

AC:

229

AN:

5768

European-Non Finnish (NFE)

AF:

0.0378

AC:

42047

AN:

1111864

Other (OTH)

AF:

0.0379

AC:

2289

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2731

5461

8192

10922

13653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1594

3188

4782

6376

7970

<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:

0.0534

AC:

8131

AN:

152194

Hom.:

289

Cov.:

AF XY:

0.0529

AC XY:

3932

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0993

AC:

4120

AN:

41510

American (AMR)

AF:

0.0334

AC:

510

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3470

East Asian (EAS)

AF:

0.0187

AC:

AN:

5180

South Asian (SAS)

AF:

0.0189

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0387

AC:

410

AN:

10588

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0392

AC:

2666

AN:

68024

Other (OTH)

AF:

0.0497

AC:

105

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

379

758

1137

1516

1895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0435

Hom.:

126

Bravo

AF:

0.0556

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Colorectal cancer, hereditary nonpolyposis, type 2 (4)

Lynch syndrome (3)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.20

(source)

DANN

Benign

0.44

PhyloP100

-0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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