dbSNP rs81002830: BRCA2:c.68-7T>A (chr13-32319070-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):c.68-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,611,588 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

BRCA2
NM_000059.4 splice_region, intron

Scores

Splicing: ADA: 0.01713

Clinical Significance

Benign reviewed by expert panel U:3B:33

Conservation

PhyloP100: 0.456

Publications

35 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 13-32319070-T-A is Benign according to our data. Variant chr13-32319070-T-A is described in ClinVar as Benign. ClinVar VariationId is 52187.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00281 (428/152318) while in subpopulation AMR AF = 0.00719 (110/15298). AF 95% confidence interval is 0.0061. There are 1 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
BRCA2	NM_000059.4	MANE Select	c.68-7T>A	splice_region intron	N/A	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.68-7T>A	splice_region intron	N/A	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.68-7T>A	splice_region intron	N/A	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.68-7T>A	splice_region intron	N/A	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.68-7T>A	splice_region intron	N/A	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.-302-7T>A	splice_region intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

429

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00287

AC:

712

AN:

247874

AF XY:

0.00294

show subpopulations

Gnomad AFR exome

AF:

0.000326

Gnomad AMR exome

AF:

0.00259

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.00634

Gnomad NFE exome

AF:

0.00242

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00247

AC:

3603

AN:

1459270

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1768

AN XY:

725876

show subpopulations

African (AFR)

AF:

0.000930

AC:

AN:

33350

American (AMR)

AF:

0.00238

AC:

106

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

349

AN:

26104

East Asian (EAS)

AF:

0.000101

AC:

AN:

39670

South Asian (SAS)

AF:

0.00201

AC:

172

AN:

85666

European-Finnish (FIN)

AF:

0.00581

AC:

309

AN:

53206

Middle Eastern (MID)

AF:

0.00161

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.00218

AC:

2421

AN:

1110850

Other (OTH)

AF:

0.00335

AC:

202

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

178

357

535

714

892

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:

0.00281

AC:

428

AN:

152318

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41576

American (AMR)

AF:

0.00719

AC:

110

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00223

AC:

152

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00363

Hom.:

Bravo

AF:

0.00229

EpiCase

AF:

0.00311

EpiControl

AF:

0.00296

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not specified (6)

Hereditary breast ovarian cancer syndrome (5)

Hereditary cancer-predisposing syndrome (4)

not provided (3)

Familial cancer of breast (2)

BRCA2-related disorder (1)

Breast and/or ovarian cancer (1)

Fanconi anemia complementation group D1 (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.6

(source)

DANN

Benign

0.65

PhyloP100

0.46

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.017

dbscSNV1_RF

Benign

0.10

Splicevardb

3.0

SpliceAI score (max)

0.050

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