rs8176233

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007294.4(BRCA1):c.4987-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 974,970 control chromosomes in the GnomAD database, including 56,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.31 ( 7679 hom., cov: 27)

Exomes 𝑓: 0.33 ( 48337 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:9O:1

Conservation

PhyloP100: -2.04

Publications

24 publications found

Variant links:

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
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

BRCA1 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=-1.04).

BP6

Variant 17-43067787-T-C is Benign according to our data. Variant chr17-43067787-T-C is described in ClinVar as Benign. ClinVar VariationId is 125749.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4987-92A>G		intron_variant	Intron 15 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4987-92A>G		intron_variant	Intron 15 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

46858

AN:

149172

Hom.:

7674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.283

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.487

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.331

GnomAD4 exome

AF:

0.334

AC:

276116

AN:

825700

Hom.:

48337

AF XY:

0.343

AC XY:

148714

AN XY:

433944

show subpopulations

African (AFR)

AF:

0.229

AC:

4694

AN:

20514

American (AMR)

AF:

0.322

AC:

12764

AN:

39616

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

7831

AN:

21398

East Asian (EAS)

AF:

0.354

AC:

12203

AN:

34470

South Asian (SAS)

AF:

0.494

AC:

35325

AN:

71460

European-Finnish (FIN)

AF:

0.395

AC:

17114

AN:

43328

Middle Eastern (MID)

AF:

0.372

AC:

1126

AN:

3026

European-Non Finnish (NFE)

AF:

0.311

AC:

172174

AN:

553348

Other (OTH)

AF:

0.334

AC:

12885

AN:

38540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

8962

17925

26887

35850

44812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3604

7208

10812

14416

18020

<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:

0.314

AC:

46888

AN:

149270

Hom.:

7679

Cov.:

AF XY:

0.319

AC XY:

23141

AN XY:

72518

show subpopulations

African (AFR)

AF:

0.232

AC:

9406

AN:

40490

American (AMR)

AF:

0.324

AC:

4814

AN:

14870

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1253

AN:

3464

East Asian (EAS)

AF:

0.369

AC:

1856

AN:

5036

South Asian (SAS)

AF:

0.486

AC:

2298

AN:

4730

European-Finnish (FIN)

AF:

0.392

AC:

3829

AN:

9776

Middle Eastern (MID)

AF:

0.351

AC:

101

AN:

288

European-Non Finnish (NFE)

AF:

0.331

AC:

22380

AN:

67640

Other (OTH)

AF:

0.336

AC:

696

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1464

2927

4391

5854

7318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.316

Hom.:

4529

Bravo

AF:

0.303

Asia WGS

AF:

0.415

AC:

1443

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:3Other:1

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3322 (Asian), 0.2175 (African), 0.3615 (European), derived from 1000 genomes (2012-04-30).

Breast Cancer Information Core (BIC) (BRCA1)

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.20

(source)

DANN

Benign

0.37

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over