NM_000059.4:c.1910-51G>T

Variant names:

Variant summary

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

The NM_000059.4(BRCA2):c.1910-51G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,549,260 control chromosomes in the GnomAD database, including 2,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.041 ( 216 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1841 hom. )

Consequence

BRCA2
NM_000059.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.0290

Publications

18 publications found

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 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 13-32336214-G-T is Benign according to our data. Variant chr13-32336214-G-T is described in ClinVar as Benign. ClinVar VariationId is 209688.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA2	NM_000059.4	MANE Select	c.1910-51G>T	intron	N/A	NP_000050.3
BRCA2	NM_001432077.1		c.1910-51G>T	intron	N/A	NP_001419006.1
BRCA2	NM_001406720.1		c.1910-51G>T	intron	N/A	NP_001393649.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.1910-51G>T	intron	N/A	ENSP00000369497.3
BRCA2	ENST00000544455.6	TSL:1	c.1910-51G>T	intron	N/A	ENSP00000439902.1
BRCA2	ENST00000530893.7	TSL:1	c.1541-51G>T	intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.0408

AC:

6210

AN:

152100

Hom.:

213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0973

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.0988

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0465

GnomAD2 exomes

AF:

0.0506

AC:

10617

AN:

209908

AF XY:

0.0531

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.0724

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.0339

Gnomad OTH exome

AF:

0.0497

GnomAD4 exome

AF:

0.0417

AC:

58223

AN:

1397042

Hom.:

1841

Cov.:

AF XY:

0.0441

AC XY:

30615

AN XY:

694330

show subpopulations

African (AFR)

AF:

0.0200

AC:

623

AN:

31208

American (AMR)

AF:

0.0760

AC:

2770

AN:

36466

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

958

AN:

23526

East Asian (EAS)

AF:

0.119

AC:

4682

AN:

39382

South Asian (SAS)

AF:

0.114

AC:

8845

AN:

77550

European-Finnish (FIN)

AF:

0.0152

AC:

789

AN:

51964

Middle Eastern (MID)

AF:

0.0629

AC:

249

AN:

3956

European-Non Finnish (NFE)

AF:

0.0341

AC:

36675

AN:

1075214

Other (OTH)

AF:

0.0456

AC:

2632

AN:

57776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2791

5582

8373

11164

13955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1502

3004

4506

6008

7510

<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:

0.0409

AC:

6229

AN:

152218

Hom.:

216

Cov.:

AF XY:

0.0436

AC XY:

3242

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0214

AC:

888

AN:

41542

American (AMR)

AF:

0.0980

AC:

1498

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

151

AN:

3470

East Asian (EAS)

AF:

0.0986

AC:

510

AN:

5172

South Asian (SAS)

AF:

0.114

AC:

549

AN:

4818

European-Finnish (FIN)

AF:

0.0148

AC:

157

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2340

AN:

68008

Other (OTH)

AF:

0.0483

AC:

102

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

303

606

909

1212

1515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0354

Hom.:

Bravo

AF:

0.0422

Asia WGS

AF:

0.110

AC:

381

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1031 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30).

not specified

Benign:2

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 01, 2017

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Hereditary cancer-predisposing syndrome

Benign:2

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Mar 07, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.4

(source)

DANN

Benign

0.53

PhyloP100

0.029

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over