Genetic Variant NM_000059.4:c.3396A>G (chr13-32337751-A-G) – 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.3396A>G(p.Lys1132Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,344 control chromosomes in the GnomAD database, including 77,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.28 ( 6327 hom., cov: 33)

Exomes 𝑓: 0.31 ( 71090 hom. )

Consequence

BRCA2
NM_000059.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:32O:1

Conservation

PhyloP100: 0.233

Publications

108 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=-0.64).

BP6

Variant 13-32337751-A-G is Benign according to our data. Variant chr13-32337751-A-G is described in ClinVar as Benign. ClinVar VariationId is 126010.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=0.233 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.3396A>G	p.Lys1132Lys	synonymous	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.3396A>G	p.Lys1132Lys	synonymous	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.3396A>G	p.Lys1132Lys	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.3396A>G	p.Lys1132Lys	synonymous	Exon 11 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.3396A>G	p.Lys1132Lys	synonymous	Exon 11 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.3027A>G	p.Lys1009Lys	synonymous	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43204

AN:

151908

Hom.:

6331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.276

GnomAD2 exomes

AF:

0.295

AC:

73766

AN:

250374

AF XY:

0.298

show subpopulations

Gnomad AFR exome

AF:

0.228

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.297

GnomAD4 exome

AF:

0.309

AC:

451175

AN:

1461318

Hom.:

71090

Cov.:

AF XY:

0.310

AC XY:

225008

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.224

AC:

7511

AN:

33458

American (AMR)

AF:

0.216

AC:

9634

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

8004

AN:

26116

East Asian (EAS)

AF:

0.435

AC:

17277

AN:

39684

South Asian (SAS)

AF:

0.300

AC:

25857

AN:

86182

European-Finnish (FIN)

AF:

0.312

AC:

16679

AN:

53386

Middle Eastern (MID)

AF:

0.260

AC:

1498

AN:

5766

European-Non Finnish (NFE)

AF:

0.312

AC:

346392

AN:

1111674

Other (OTH)

AF:

0.303

AC:

18323

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17701

35402

53104

70805

88506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11326

22652

33978

45304

56630

<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:

0.284

AC:

43194

AN:

152026

Hom.:

6327

Cov.:

AF XY:

0.285

AC XY:

21218

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.230

AC:

9553

AN:

41488

American (AMR)

AF:

0.224

AC:

3425

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1065

AN:

3466

East Asian (EAS)

AF:

0.398

AC:

2054

AN:

5162

South Asian (SAS)

AF:

0.293

AC:

1414

AN:

4824

European-Finnish (FIN)

AF:

0.318

AC:

3354

AN:

10540

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.316

AC:

21505

AN:

67950

Other (OTH)

AF:

0.273

AC:

577

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1592

3183

4775

6366

7958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.308

Hom.:

15197

Bravo

AF:

0.274

Asia WGS

AF:

0.280

AC:

975

AN:

3478

EpiCase

AF:

0.313

EpiControl

AF:

0.301

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 (8)

Hereditary breast ovarian cancer syndrome (4)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Familial cancer of breast (3)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.9

(source)

DANN

Benign

0.55

PhyloP100

0.23

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