rs1801426

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.10234A>G(p.Ile3412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,938 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3412S) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.036 ( 287 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 439 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:42O:1

Conservation

PhyloP100: 0.556

Publications

89 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):

BRCA2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017527342).

BP6

Variant 13-32398747-A-G is Benign according to our data. Variant chr13-32398747-A-G is described in ClinVar as Benign. ClinVar VariationId is 41540.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 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	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	NM_000059.4	MANE Select	c.10234A>G	p.Ile3412Val	missense	Exon 27 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.10234A>G	p.Ile3412Val	missense	Exon 27 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.10183A>G	p.Ile3395Val	missense	Exon 27 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.10234A>G	p.Ile3412Val	missense	Exon 27 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.10234A>G	p.Ile3412Val	missense	Exon 27 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.9865A>G	p.Ile3289Val	missense	Exon 27 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

5525

AN:

152176

Hom.:

283

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0453

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0233

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00876

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0233

AC:

5843

AN:

250706

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.0905

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0240

Gnomad FIN exome

AF:

0.00801

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.00751

AC:

10984

AN:

1461644

Hom.:

439

Cov.:

AF XY:

0.00670

AC XY:

4869

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.115

AC:

3832

AN:

33460

American (AMR)

AF:

0.0843

AC:

3766

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26134

East Asian (EAS)

AF:

0.0215

AC:

853

AN:

39684

South Asian (SAS)

AF:

0.00233

AC:

201

AN:

86202

European-Finnish (FIN)

AF:

0.00708

AC:

378

AN:

53382

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00101

AC:

1118

AN:

1111960

Other (OTH)

AF:

0.0120

AC:

727

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

523

1045

1568

2090

2613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0364

AC:

5536

AN:

152294

Hom.:

287

Cov.:

AF XY:

0.0366

AC XY:

2728

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.107

AC:

4427

AN:

41540

American (AMR)

AF:

0.0456

AC:

697

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0233

AC:

121

AN:

5190

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00876

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68030

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

254

509

763

1018

1272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0132

Hom.:

350

Bravo

AF:

0.0447

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.106

AC:

469

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.0223

AC:

2714

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (11)

not specified (11)

Hereditary cancer-predisposing syndrome (5)

not provided (5)

Hereditary breast ovarian cancer syndrome (4)

Familial cancer of breast (3)

BRCA2-related cancer predisposition (1)

Breast and/or ovarian cancer (1)

Breast neoplasm (1)

Fanconi anemia complementation group D1 (1)

Malignant tumor of breast (1)

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.47

(source)

DANN

Benign

0.49

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.019

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.93

PhyloP100

0.56

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.090

REVEL

Benign

0.028

Sift

Benign

0.92

Sift4G

Benign

0.35

Vest4

0.020

MPC

0.020

ClinPred

0.00057

GERP RS

-0.29

gMVP

0.018

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

Computational scores

Splicing

Publications

Other links and lift over