NM_000059.4:c.1114A>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.1114A>C(p.Asn372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,613,510 control chromosomes in the GnomAD database, including 63,594 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. N372Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 4773 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58821 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:37O:2

Conservation

PhyloP100: 0.320

Publications

337 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 (MetaRNN=0.005027443).

BP6

Variant 13-32332592-A-C is Benign according to our data. Variant chr13-32332592-A-C is described in ClinVar as Benign. ClinVar VariationId is 9329.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 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
BRCA2	NM_000059.4	MANE Select	c.1114A>C	p.Asn372His	missense	Exon 10 of 27	NP_000050.3
BRCA2	NM_001432077.1		c.1114A>C	p.Asn372His	missense	Exon 10 of 27	NP_001419006.1
BRCA2	NM_001406720.1		c.1114A>C	p.Asn372His	missense	Exon 10 of 27	NP_001393649.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.1114A>C	p.Asn372His	missense	Exon 10 of 27	ENSP00000369497.3
BRCA2	ENST00000544455.6	TSL:1	c.1114A>C	p.Asn372His	missense	Exon 10 of 27	ENSP00000439902.1
BRCA2	ENST00000530893.7	TSL:1	c.745A>C	p.Asn249His	missense	Exon 10 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36156

AN:

151966

Hom.:

4768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.360

Gnomad EAS

AF:

0.258

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.280

AC:

69869

AN:

249852

AF XY:

0.285

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.304

Gnomad ASJ exome

AF:

0.356

Gnomad EAS exome

AF:

0.267

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.281

AC:

409992

AN:

1461426

Hom.:

58821

Cov.:

AF XY:

0.283

AC XY:

205796

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.125

AC:

4191

AN:

33460

American (AMR)

AF:

0.302

AC:

13480

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

9224

AN:

26114

East Asian (EAS)

AF:

0.236

AC:

9379

AN:

39684

South Asian (SAS)

AF:

0.349

AC:

30093

AN:

86138

European-Finnish (FIN)

AF:

0.232

AC:

12392

AN:

53404

Middle Eastern (MID)

AF:

0.301

AC:

1735

AN:

5768

European-Non Finnish (NFE)

AF:

0.281

AC:

312835

AN:

1111836

Other (OTH)

AF:

0.276

AC:

16663

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

17797

35595

53392

71190

88987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10532

21064

31596

42128

52660

<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:

0.238

AC:

36183

AN:

152084

Hom.:

4773

Cov.:

AF XY:

0.239

AC XY:

17733

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.125

AC:

5198

AN:

41508

American (AMR)

AF:

0.304

AC:

4642

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

1251

AN:

3472

East Asian (EAS)

AF:

0.258

AC:

1338

AN:

5184

South Asian (SAS)

AF:

0.358

AC:

1722

AN:

4814

European-Finnish (FIN)

AF:

0.221

AC:

2341

AN:

10570

Middle Eastern (MID)

AF:

0.260

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.276

AC:

18783

AN:

67950

Other (OTH)

AF:

0.267

AC:

563

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1383

2766

4150

5533

6916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.271

Hom.:

27773

Bravo

AF:

0.238

TwinsUK

AF:

0.282

AC:

1046

ALSPAC

AF:

0.284

AC:

1096

ESP6500AA

AF:

0.129

AC:

558

ESP6500EA

AF:

0.286

AC:

2449

ExAC

AF:

0.277

AC:

33603

Asia WGS

AF:

0.339

AC:

1177

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.281

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (12)

not specified (9)

not provided (6)

Hereditary breast ovarian cancer syndrome (4)

Hereditary cancer-predisposing syndrome (3)

Familial cancer of breast (2)

BRCA2-related cancer predisposition (1)

Breast carcinoma (1)

Breast ductal adenocarcinoma (1)

Fanconi anemia complementation group D1 (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

0.070

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.087

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.95

PhyloP100

0.32

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.60

REVEL

Benign

0.041

Sift

Benign

0.14

Sift4G

Benign

0.34

Vest4

0.081

MPC

0.021

ClinPred

0.0012

GERP RS

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.054

Mutation Taster

=99/1

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