rs641936

Variant names:

Variant summary

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

The NM_005591.4(MRE11):c.1225+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,608,042 control chromosomes in the GnomAD database, including 102,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10427 hom., cov: 32)

Exomes 𝑓: 0.35 ( 91640 hom. )

Consequence

MRE11
NM_005591.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.49

Publications

18 publications found

Variant links:

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MRE11 Gene-Disease associations (from GenCC):

ataxia-telangiectasia-like disorder 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
prostate cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

MRE11 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=-0.93).

BP6

Variant 11-94464094-A-G is Benign according to our data. Variant chr11-94464094-A-G is described in ClinVar as Benign. ClinVar VariationId is 193884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.1225+19T>C		intron_variant	Intron 11 of 19	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
MRE11	ENST00000323929.8 link	c.1225+19T>C	intron_variant	Intron 11 of 19	1	NM_005591.4	ENSP00000325863.4
MRE11	ENST00000323977.7 link	c.1225+19T>C	intron_variant	Intron 11 of 18	1		ENSP00000326094.3
MRE11	ENST00000407439.7 link	c.1234+19T>C	intron_variant	Intron 11 of 19	2		ENSP00000385614.3
MRE11	ENST00000393241.8 link	c.1225+19T>C	intron_variant	Intron 11 of 19	5		ENSP00000376933.4

Frequencies

GnomAD3 genomes

AF:

0.369

AC:

55979

AN:

151908

Hom.:

10417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.213

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.365

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.342

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.382

AC:

95495

AN:

250300

AF XY:

0.382

show subpopulations

Gnomad AFR exome

AF:

0.371

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.387

Gnomad EAS exome

AF:

0.407

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.345

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.352

AC:

512471

AN:

1456014

Hom.:

91640

Cov.:

AF XY:

0.354

AC XY:

256805

AN XY:

724550

show subpopulations

African (AFR)

AF:

0.390

AC:

12983

AN:

33302

American (AMR)

AF:

0.445

AC:

19869

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9992

AN:

26076

East Asian (EAS)

AF:

0.421

AC:

16635

AN:

39538

South Asian (SAS)

AF:

0.426

AC:

36617

AN:

85994

European-Finnish (FIN)

AF:

0.386

AC:

20570

AN:

53336

Middle Eastern (MID)

AF:

0.438

AC:

2020

AN:

4610

European-Non Finnish (NFE)

AF:

0.336

AC:

372051

AN:

1108420

Other (OTH)

AF:

0.362

AC:

21734

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

15264

30529

45793

61058

76322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12102

24204

36306

48408

60510

<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:

0.368

AC:

56020

AN:

152028

Hom.:

10427

Cov.:

AF XY:

0.374

AC XY:

27762

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.377

AC:

15642

AN:

41478

American (AMR)

AF:

0.419

AC:

6402

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

1266

AN:

3466

East Asian (EAS)

AF:

0.401

AC:

2075

AN:

5176

South Asian (SAS)

AF:

0.421

AC:

2031

AN:

4828

European-Finnish (FIN)

AF:

0.399

AC:

4204

AN:

10538

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.342

AC:

23255

AN:

67964

Other (OTH)

AF:

0.385

AC:

813

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1816

3632

5447

7263

9079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.356

Hom.:

1821

Bravo

AF:

0.370

Asia WGS

AF:

0.380

AC:

1322

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.1225+19T>C in MRE11A gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.378 (45400/120008 chrs tested), including numerous homozygous occurrence. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.006%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign/Polymorphism by reputable databases/clinical laboratory and in published reports (Bartkova, 2008). Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia-like disorder 1

Benign:2

Apr 14, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia-like disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.11

(source)

DANN

Benign

0.68

PhyloP100

-1.5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over