chr13-32398489-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BA1BP5_StrongBS3

This summary comes from the ClinGen Evidence Repository: The c.9976A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID:18451181, Internal lab contributor).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA026350/MONDO:0012933/097

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 69 hom. )

Consequence

BRCA2
NM_000059.4 stop_gained

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:49O:2

Conservation

PhyloP100: 0.723

Publications

298 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 -16 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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.9976A>T	p.Lys3326*	stop_gained	Exon 27 of 27	NP_000050.3
BRCA2	NM_001432077.1		c.9976A>T	p.Lys3326*	stop_gained	Exon 27 of 27	NP_001419006.1
BRCA2	NM_001406720.1		c.9925A>T	p.Lys3309*	stop_gained	Exon 27 of 27	NP_001393649.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9976A>T	p.Lys3326*	stop_gained	Exon 27 of 27	ENSP00000369497.3
BRCA2	ENST00000544455.6	TSL:1	c.9976A>T	p.Lys3326*	stop_gained	Exon 27 of 27	ENSP00000439902.1
BRCA2	ENST00000530893.7	TSL:1	c.9607A>T	p.Lys3203*	stop_gained	Exon 27 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

915

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00849

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00660

AC:

1654

AN:

250748

AF XY:

0.00683

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.00895

Gnomad OTH exome

AF:

0.00688

GnomAD4 exome

AF:

0.00812

AC:

11863

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

6006

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33458

American (AMR)

AF:

0.00266

AC:

119

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

117

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00650

AC:

561

AN:

86256

European-Finnish (FIN)

AF:

0.00985

AC:

526

AN:

53410

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00901

AC:

10022

AN:

1111978

Other (OTH)

AF:

0.00725

AC:

438

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

698

1396

2094

2792

3490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.00600

AC:

914

AN:

152362

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

436

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

41586

American (AMR)

AF:

0.00510

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00683

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0104

AC:

111

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00850

AC:

578

AN:

68036

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00705

Hom.:

Bravo

AF:

0.00539

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.00701

AC:

851

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00960

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 (15)

not specified (12)

not provided (9)

Hereditary breast ovarian cancer syndrome (5)

Hereditary cancer-predisposing syndrome (4)

Breast and/or ovarian cancer (2)

Malignant tumor of breast (2)

BRCA2-related cancer predisposition (1)

Familial cancer of breast (1)

Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

Eigen

Benign

0.0040

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.044

PhyloP100

0.72

Vest4

0.64

GERP RS

0.16

Mutation Taster

=142/58

disease causing (fs/PTC)

(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