NM_007294.4:c.2077G>A

Variant names:

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.2077G>A(p.Asp693Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0698 in 1,613,950 control chromosomes in the GnomAD database, including 4,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D693E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.057 ( 338 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4107 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:34O:1

Conservation

PhyloP100: 0.205

Publications

148 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):

BRCA1-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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 (MetaRNN=0.0017115176).

BP6

Variant 17-43093454-C-T is Benign according to our data. Variant chr17-43093454-C-T is described in ClinVar as Benign. ClinVar VariationId is 41808.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	NM_007294.4	MANE Select	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.2077G>A	p.Asp693Asn	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.2077G>A	p.Asp693Asn	missense	Exon 10 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0569

AC:

8658

AN:

152126

Hom.:

338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0231

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0536

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0323

Gnomad FIN

AF:

0.0960

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0767

Gnomad OTH

AF:

0.0608

GnomAD2 exomes

AF:

0.0584

AC:

14674

AN:

251126

AF XY:

0.0596

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0941

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0898

Gnomad NFE exome

AF:

0.0772

Gnomad OTH exome

AF:

0.0658

GnomAD4 exome

AF:

0.0711

AC:

103938

AN:

1461706

Hom.:

4107

Cov.:

AF XY:

0.0697

AC XY:

50660

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.0234

AC:

782

AN:

33480

American (AMR)

AF:

0.0360

AC:

1609

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

2408

AN:

26130

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.0359

AC:

3100

AN:

86240

European-Finnish (FIN)

AF:

0.0862

AC:

4598

AN:

53364

Middle Eastern (MID)

AF:

0.0742

AC:

428

AN:

5768

European-Non Finnish (NFE)

AF:

0.0782

AC:

86992

AN:

1111924

Other (OTH)

AF:

0.0665

AC:

4017

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5912

11823

17735

23646

29558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3170

6340

9510

12680

15850

<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:

0.0568

AC:

8651

AN:

152244

Hom.:

338

Cov.:

AF XY:

0.0566

AC XY:

4215

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0230

AC:

954

AN:

41540

American (AMR)

AF:

0.0534

AC:

817

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0862

AC:

299

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.0319

AC:

154

AN:

4830

European-Finnish (FIN)

AF:

0.0960

AC:

1017

AN:

10598

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0767

AC:

5214

AN:

68004

Other (OTH)

AF:

0.0601

AC:

127

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

413

825

1238

1650

2063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0685

Hom.:

1334

Bravo

AF:

0.0536

TwinsUK

AF:

0.0836

AC:

310

ALSPAC

AF:

0.0890

AC:

343

ESP6500AA

AF:

0.0232

AC:

102

ESP6500EA

AF:

0.0702

AC:

604

ExAC

AF:

0.0568

AC:

6894

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0778

EpiControl

AF:

0.0835

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (10)

not specified (8)

not provided (5)

Hereditary breast ovarian cancer syndrome (4)

Hereditary cancer-predisposing syndrome (4)

Familial cancer of breast (2)

BRCA1-related cancer predisposition (1)

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Benign

7.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

PhyloP100

0.20

PrimateAI

Benign

0.23

PROVEAN

Benign

0.030

REVEL

Benign

0.13

Sift

Uncertain

0.012

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.21

MPC

0.080

ClinPred

0.0054

GERP RS

1.2

Varity_R

0.046

gMVP

0.077

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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