13-32329548-C-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.681+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,307,266 control chromosomes in the GnomAD database, including 24,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.21 ( 3387 hom., cov: 32)

Exomes 𝑓: 0.19 ( 21607 hom. )

Consequence

BRCA2
NM_000059.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:14

Conservation

PhyloP100: -0.265

Publications

36 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=-0.8).

BP6

Variant 13-32329548-C-T is Benign according to our data. Variant chr13-32329548-C-T is described in ClinVar as Benign. ClinVar VariationId is 126192.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.681+56C>T		intron_variant	Intron 8 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.681+56C>T	intron_variant	Intron 8 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.312+56C>T	intron_variant	Intron 8 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.681+56C>T	intron_variant	Intron 7 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31123

AN:

151760

Hom.:

3378

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.222

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0824

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.188

Gnomad OTH

AF:

0.191

GnomAD4 exome

AF:

0.188

AC:

217330

AN:

1155390

Hom.:

21607

AF XY:

0.185

AC XY:

108379

AN XY:

584296

show subpopulations

African (AFR)

AF:

0.244

AC:

6597

AN:

27056

American (AMR)

AF:

0.227

AC:

9133

AN:

40224

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

3978

AN:

23504

East Asian (EAS)

AF:

0.0576

AC:

2162

AN:

37562

South Asian (SAS)

AF:

0.134

AC:

10153

AN:

75618

European-Finnish (FIN)

AF:

0.256

AC:

13141

AN:

51238

Middle Eastern (MID)

AF:

0.143

AC:

724

AN:

5076

European-Non Finnish (NFE)

AF:

0.192

AC:

161896

AN:

845158

Other (OTH)

AF:

0.191

AC:

9546

AN:

49954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

8390

16779

25169

33558

41948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5118

10236

15354

20472

25590

<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:

0.205

AC:

31170

AN:

151876

Hom.:

3387

Cov.:

AF XY:

0.204

AC XY:

15168

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.250

AC:

10337

AN:

41408

American (AMR)

AF:

0.204

AC:

3114

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

571

AN:

3468

East Asian (EAS)

AF:

0.0830

AC:

429

AN:

5168

South Asian (SAS)

AF:

0.127

AC:

610

AN:

4814

European-Finnish (FIN)

AF:

0.254

AC:

2675

AN:

10540

Middle Eastern (MID)

AF:

0.147

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.188

AC:

12789

AN:

67906

Other (OTH)

AF:

0.189

AC:

400

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1243

2486

3730

4973

6216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.190

Hom.:

4104

Bravo

AF:

0.206

Asia WGS

AF:

0.141

AC:

489

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:4

Apr 12, 1999

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control 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 0.07343 (Asian), 0.313 (African), 0.2018 (European), derived from 1000 genomes (2012-04-30). -

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Nov 01, 2017

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

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. -

Dec 09, 2014

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:2

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

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial cancer of breast

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

-0.80

CADD

Benign

7.0

(source)

DANN

Benign

0.63

PhyloP100

-0.27

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