13-32325251-A-C

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.425+67A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,200,608 control chromosomes in the GnomAD database, including 1,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.041 ( 222 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1561 hom. )

Consequence

BRCA2
NM_000059.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:13

Conservation

PhyloP100: 1.98

Publications

19 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=-0.79).

BP6

Variant 13-32325251-A-C is Benign according to our data. Variant chr13-32325251-A-C is described in ClinVar as Benign. ClinVar VariationId is 126095.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.425+67A>C		intron_variant	Intron 4 of 26	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.425+67A>C	intron_variant	Intron 4 of 26	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.56+67A>C	intron_variant	Intron 4 of 26	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.425+67A>C	intron_variant	Intron 3 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0410

AC:

6237

AN:

152176

Hom.:

219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0980

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0478

GnomAD4 exome

AF:

0.0441

AC:

46224

AN:

1048314

Hom.:

1561

AF XY:

0.0470

AC XY:

24918

AN XY:

530522

show subpopulations

African (AFR)

AF:

0.0210

AC:

503

AN:

23898

American (AMR)

AF:

0.0800

AC:

2655

AN:

33202

Ashkenazi Jewish (ASJ)

AF:

0.0416

AC:

936

AN:

22502

East Asian (EAS)

AF:

0.123

AC:

4112

AN:

33564

South Asian (SAS)

AF:

0.117

AC:

7907

AN:

67808

European-Finnish (FIN)

AF:

0.0153

AC:

617

AN:

40280

Middle Eastern (MID)

AF:

0.0611

AC:

209

AN:

3420

European-Non Finnish (NFE)

AF:

0.0349

AC:

27118

AN:

777488

Other (OTH)

AF:

0.0470

AC:

2167

AN:

46152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

2104

4209

6313

8418

10522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

966

1932

2898

3864

4830

<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:

0.0411

AC:

6256

AN:

152294

Hom.:

222

Cov.:

AF XY:

0.0437

AC XY:

3256

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0213

AC:

886

AN:

41574

American (AMR)

AF:

0.0987

AC:

1509

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3470

East Asian (EAS)

AF:

0.100

AC:

519

AN:

5184

South Asian (SAS)

AF:

0.115

AC:

554

AN:

4832

European-Finnish (FIN)

AF:

0.0144

AC:

153

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2343

AN:

68018

Other (OTH)

AF:

0.0497

AC:

105

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

306

611

917

1222

1528

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:

0.0351

Hom.:

Bravo

AF:

0.0425

Asia WGS

AF:

0.109

AC:

376

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:4

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 0.1049 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2010

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

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

- -

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

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

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

-0.79

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

2.0

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