13-32319134-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001406722.1(BRCA2):c.-245A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,770 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

BRCA2
NM_001406722.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:38O:2

Conservation

PhyloP100: 0.845

Publications

80 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

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009805024).

BP6

Variant 13-32319134-A-G is Benign according to our data. Variant chr13-32319134-A-G is described in ClinVar as Benign. ClinVar VariationId is 37734.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406722.1. 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.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001406722.1		c.-245A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 24	NP_001393651.1
BRCA2	NM_001432077.1		c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	NP_001419006.1	A0A7P0T9D7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000530893.7	TSL:1	c.-245A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 27	ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	ENSP00000439902.1	P51587

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00163

AC:

409

AN:

251278

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00213

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00213

AC:

3109

AN:

1461456

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1563

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33464

American (AMR)

AF:

0.00116

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39680

South Asian (SAS)

AF:

0.00238

AC:

205

AN:

86254

European-Finnish (FIN)

AF:

0.00251

AC:

134

AN:

53404

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00227

AC:

2521

AN:

1111648

Other (OTH)

AF:

0.00222

AC:

134

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

172

344

515

687

859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00152

AC:

232

AN:

152314

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41558

American (AMR)

AF:

0.000457

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00248

AC:

169

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00195

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00169

AC:

205

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (13)

not specified (11)

not provided (5)

Hereditary breast ovarian cancer syndrome (4)

Hereditary cancer-predisposing syndrome (4)

Familial cancer of breast (2)

BRCA2-related cancer predisposition (1)

Breast and/or ovarian cancer (1)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.6

(source)

DANN

Benign

0.49

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.93

FATHMM_MKL

Uncertain

0.76

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.76

PhyloP100

0.84

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

REVEL

Benign

0.089

Sift

Benign

0.11

Sift4G

Benign

0.11

Vest4

0.31

MVP

0.78

MPC

0.023

ClinPred

0.0018

GERP RS

0.28

gMVP

0.40

Mutation Taster

=80/20

polymorphism

(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