chr17-43071077-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.4837A>G(p.Ser1613Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,613,902 control chromosomes in the GnomAD database, including 94,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. S1613D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 8007 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86242 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:35O:2

Conservation

PhyloP100: -0.194

Publications

316 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=3.0711293E-4).

BP6

Variant 17-43071077-T-C is Benign according to our data. Variant chr17-43071077-T-C is described in ClinVar as Benign. ClinVar VariationId is 41827.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.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.4903A>G	p.Ser1635Gly	missense	Exon 16 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.4903A>G	p.Ser1635Gly	missense	Exon 16 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.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.4900A>G	p.Ser1634Gly	missense	Exon 16 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48290

AN:

151926

Hom.:

8001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.354

AC:

88974

AN:

251384

AF XY:

0.362

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.317

Gnomad ASJ exome

AF:

0.374

Gnomad EAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.348

GnomAD4 exome

AF:

0.340

AC:

496800

AN:

1461858

Hom.:

86242

Cov.:

AF XY:

0.345

AC XY:

250799

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.233

AC:

7805

AN:

33480

American (AMR)

AF:

0.321

AC:

14344

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

9616

AN:

26136

East Asian (EAS)

AF:

0.353

AC:

14028

AN:

39698

South Asian (SAS)

AF:

0.499

AC:

43064

AN:

86256

European-Finnish (FIN)

AF:

0.396

AC:

21175

AN:

53416

Middle Eastern (MID)

AF:

0.373

AC:

2154

AN:

5768

European-Non Finnish (NFE)

AF:

0.327

AC:

364076

AN:

1111986

Other (OTH)

AF:

0.340

AC:

20538

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

21821

43642

65462

87283

109104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11924

23848

35772

47696

59620

<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:

0.318

AC:

48324

AN:

152044

Hom.:

8007

Cov.:

AF XY:

0.324

AC XY:

24084

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.237

AC:

9828

AN:

41468

American (AMR)

AF:

0.330

AC:

5029

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1256

AN:

3468

East Asian (EAS)

AF:

0.370

AC:

1917

AN:

5178

South Asian (SAS)

AF:

0.492

AC:

2370

AN:

4816

European-Finnish (FIN)

AF:

0.404

AC:

4268

AN:

10558

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22581

AN:

67976

Other (OTH)

AF:

0.337

AC:

711

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1667

3334

5001

6668

8335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<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:

0.325

Hom.:

29484

Bravo

AF:

0.303

TwinsUK

AF:

0.339

AC:

1258

ALSPAC

AF:

0.337

AC:

1300

ESP6500AA

AF:

0.243

AC:

1069

ESP6500EA

AF:

0.327

AC:

2809

ExAC

AF:

0.349

AC:

42424

Asia WGS

AF:

0.411

AC:

1430

AN:

3478

EpiCase

AF:

0.324

EpiControl

AF:

0.333

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 (9)

Hereditary breast ovarian cancer syndrome (4)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Familial cancer of breast (2)

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

0.084

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Benign

6.9

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.59

MetaRNN

Benign

0.00031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

-0.19

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

REVEL

Benign

0.25

Sift

Benign

0.040

Sift4G

Benign

0.19

Polyphen

0.26

Vest4

0.30

MPC

0.076

ClinPred

0.0023

GERP RS

1.5

Varity_R

0.057

gMVP

0.23

Mutation Taster

=98/2

polymorphism (auto)

(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