17-43092418-T-C

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.3113A>G(p.Glu1038Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,370 control chromosomes in the GnomAD database, including 92,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. E1038D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 7403 hom., cov: 31)

Exomes 𝑓: 0.34 ( 85235 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:36O:2

Conservation

PhyloP100: -0.149

Publications

263 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=2.296269E-4).

BP6

Variant 17-43092418-T-C is Benign according to our data. Variant chr17-43092418-T-C is described in ClinVar as Benign. ClinVar VariationId is 41815.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 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.3113A>G	p.Glu1038Gly	missense	Exon 10 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.3113A>G	p.Glu1038Gly	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.3113A>G	p.Glu1038Gly	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45583

AN:

151792

Hom.:

7401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.349

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.403

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.348

AC:

87427

AN:

251032

AF XY:

0.357

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.379

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.343

GnomAD4 exome

AF:

0.337

AC:

492920

AN:

1461460

Hom.:

85235

Cov.:

AF XY:

0.343

AC XY:

249016

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.175

AC:

5849

AN:

33478

American (AMR)

AF:

0.315

AC:

14072

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

9323

AN:

26130

East Asian (EAS)

AF:

0.353

AC:

13995

AN:

39682

South Asian (SAS)

AF:

0.499

AC:

43005

AN:

86246

European-Finnish (FIN)

AF:

0.396

AC:

21105

AN:

53270

Middle Eastern (MID)

AF:

0.368

AC:

2123

AN:

5768

European-Non Finnish (NFE)

AF:

0.327

AC:

363291

AN:

1111782

Other (OTH)

AF:

0.334

AC:

20157

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

21316

42632

63948

85264

106580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11872

23744

35616

47488

59360

<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:

0.300

AC:

45589

AN:

151910

Hom.:

7403

Cov.:

AF XY:

0.307

AC XY:

22773

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.180

AC:

7456

AN:

41456

American (AMR)

AF:

0.319

AC:

4864

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

1210

AN:

3468

East Asian (EAS)

AF:

0.369

AC:

1910

AN:

5180

South Asian (SAS)

AF:

0.492

AC:

2363

AN:

4802

European-Finnish (FIN)

AF:

0.403

AC:

4234

AN:

10508

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22507

AN:

67942

Other (OTH)

AF:

0.324

AC:

685

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1562

3124

4687

6249

7811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.315

Hom.:

26706

Bravo

AF:

0.283

TwinsUK

AF:

0.339

AC:

1256

ALSPAC

AF:

0.336

AC:

1294

ESP6500AA

AF:

0.188

AC:

830

ESP6500EA

AF:

0.325

AC:

2799

ExAC

AF:

0.343

AC:

41615

Asia WGS

AF:

0.405

AC:

1408

AN:

3474

EpiCase

AF:

0.323

EpiControl

AF:

0.332

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (11)

not specified (10)

Familial cancer of breast (4)

Hereditary breast ovarian cancer syndrome (4)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

BRCA1-related cancer predisposition (1)

Breast carcinoma (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)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.66

MetaRNN

Benign

0.00023

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

-0.15

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.7

REVEL

Benign

0.23

Sift

Uncertain

0.028

Sift4G

Uncertain

0.028

Polyphen

0.94

Vest4

0.28

MPC

0.24

ClinPred

0.031

GERP RS

-0.97

Varity_R

0.13

gMVP

0.21

Mutation Taster

=98/2

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

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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