dbSNP rs543304: BRCA2:p.Val1269Val (chr13-32338162-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000059.4(BRCA2):c.3807T>C(p.Val1269Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,589,028 control chromosomes in the GnomAD database, including 25,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. V1269V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2553 hom., cov: 33)

Exomes 𝑓: 0.18 ( 22866 hom. )

Consequence

BRCA2
NM_000059.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:31

Conservation

PhyloP100: -0.00500

Publications

99 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 13-32338162-T-C is Benign according to our data. Variant chr13-32338162-T-C is described in ClinVar as Benign. ClinVar VariationId is 126022.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-0.005 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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.3807T>C	p.Val1269Val	synonymous	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.3807T>C	p.Val1269Val	synonymous	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.3807T>C	p.Val1269Val	synonymous	Exon 11 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.3807T>C	p.Val1269Val	synonymous	Exon 11 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.3807T>C	p.Val1269Val	synonymous	Exon 11 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.3438T>C	p.Val1146Val	synonymous	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27533

AN:

152002

Hom.:

2552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.175

AC:

40549

AN:

232236

AF XY:

0.172

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.192

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.176

AC:

253327

AN:

1436908

Hom.:

22866

Cov.:

AF XY:

0.174

AC XY:

123845

AN XY:

713570

show subpopulations

African (AFR)

AF:

0.198

AC:

6407

AN:

32390

American (AMR)

AF:

0.172

AC:

6966

AN:

40584

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3515

AN:

25376

East Asian (EAS)

AF:

0.151

AC:

5952

AN:

39500

South Asian (SAS)

AF:

0.102

AC:

8354

AN:

81742

European-Finnish (FIN)

AF:

0.185

AC:

9782

AN:

52820

Middle Eastern (MID)

AF:

0.235

AC:

1328

AN:

5648

European-Non Finnish (NFE)

AF:

0.183

AC:

200700

AN:

1099486

Other (OTH)

AF:

0.174

AC:

10323

AN:

59362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10176

20353

30529

40706

50882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6996

13992

20988

27984

34980

<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:

0.181

AC:

27538

AN:

152120

Hom.:

2553

Cov.:

AF XY:

0.179

AC XY:

13289

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.191

AC:

7928

AN:

41508

American (AMR)

AF:

0.158

AC:

2408

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

460

AN:

3470

East Asian (EAS)

AF:

0.161

AC:

830

AN:

5170

South Asian (SAS)

AF:

0.110

AC:

529

AN:

4828

European-Finnish (FIN)

AF:

0.191

AC:

2026

AN:

10590

Middle Eastern (MID)

AF:

0.236

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.186

AC:

12641

AN:

67974

Other (OTH)

AF:

0.186

AC:

392

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1152

2305

3457

4610

5762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.184

Hom.:

7869

Bravo

AF:

0.183

Asia WGS

AF:

0.116

AC:

404

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (10)

not specified (8)

Hereditary breast ovarian cancer syndrome (4)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Familial cancer of breast (2)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.78

(source)

DANN

Benign

0.47

PhyloP100

-0.0050

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