rs1800744

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007294.4(BRCA1):c.4535G>T(p.Ser1512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,128 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. S1512C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 17 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:40O:1

Conservation

PhyloP100: 3.21

Publications

76 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031846404).

BP6

Variant 17-43074471-C-A is Benign according to our data. Variant chr17-43074471-C-A is described in ClinVar as Benign. ClinVar VariationId is 41826.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Homozygotes in GnomAdExome4 at 17 AR,AD gene

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.4535G>T	p.Ser1512Ile	missense	Exon 14 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.4601G>T	p.Ser1534Ile	missense	Exon 15 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.4601G>T	p.Ser1534Ile	missense	Exon 15 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.4535G>T	p.Ser1512Ile	missense	Exon 14 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.4598G>T	p.Ser1533Ile	missense	Exon 15 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.4535G>T	p.Ser1512Ile	missense	Exon 14 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00237

AC:

596

AN:

251366

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00316

AC:

4625

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2251

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33478

American (AMR)

AF:

0.00157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00555

AC:

145

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00367

AC:

4080

AN:

1111972

Other (OTH)

AF:

0.00273

AC:

165

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.00226

AC:

344

AN:

152284

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41550

American (AMR)

AF:

0.00111

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00382

AC:

260

AN:

68036

Other (OTH)

AF:

0.00236

AC:

AN:

2116

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:

0.00353

Hom.:

Bravo

AF:

0.00241

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00215

AC:

261

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00332

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (12)

not specified (12)

Hereditary breast ovarian cancer syndrome (5)

Hereditary cancer-predisposing syndrome (5)

not provided (5)

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

0.14

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.032

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.9

PhyloP100

3.2

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.014

Polyphen

0.34

Vest4

0.47

MVP

0.85

MPC

0.10

ClinPred

0.033

GERP RS

4.0

Varity_R

0.081

gMVP

0.41

Mutation Taster

=89/11

polymorphism

(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