17-43091983-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_001407581.1(BRCA1):c.3548A>G(p.Lys1183Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,632 control chromosomes in the GnomAD database, including 93,431 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1183E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 7893 hom., cov: 31)

Exomes 𝑓: 0.34 ( 85538 hom. )

Consequence

BRCA1
NM_001407581.1 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:35O:1

Conservation

PhyloP100: -0.319

Publications

279 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 (MetaRNN=4.872718E-5).

BP6

Variant 17-43091983-T-C is Benign according to our data. Variant chr17-43091983-T-C is described in ClinVar as Benign. ClinVar VariationId is 41818.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407581.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA1	NM_007294.4	MANE Select	c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 23	NP_009225.1
BRCA1	NM_001407581.1		c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 24	NP_001394510.1
BRCA1	NM_001407582.1		c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 24	NP_001394511.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 23	ENSP00000350283.3
BRCA1	ENST00000471181.7	TSL:1	c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 24	ENSP00000418960.2
BRCA1	ENST00000470026.6	TSL:1	c.3548A>G	p.Lys1183Arg	missense	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47926

AN:

151924

Hom.:

7887

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.494

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.334

GnomAD2 exomes

AF:

0.353

AC:

88507

AN:

250954

AF XY:

0.361

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

AF:

0.338

AC:

494457

AN:

1461590

Hom.:

85538

Cov.:

AF XY:

0.343

AC XY:

249690

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.230

AC:

7695

AN:

33472

American (AMR)

AF:

0.320

AC:

14304

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

9572

AN:

26130

East Asian (EAS)

AF:

0.353

AC:

14022

AN:

39694

South Asian (SAS)

AF:

0.499

AC:

43055

AN:

86252

European-Finnish (FIN)

AF:

0.396

AC:

21135

AN:

53368

Middle Eastern (MID)

AF:

0.371

AC:

2138

AN:

5766

European-Non Finnish (NFE)

AF:

0.326

AC:

362045

AN:

1111812

Other (OTH)

AF:

0.339

AC:

20491

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21471

42943

64414

85886

107357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11866

23732

35598

47464

59330

<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:

0.315

AC:

47960

AN:

152042

Hom.:

7893

Cov.:

AF XY:

0.322

AC XY:

23934

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.233

AC:

9647

AN:

41490

American (AMR)

AF:

0.328

AC:

5005

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1244

AN:

3466

East Asian (EAS)

AF:

0.369

AC:

1907

AN:

5164

South Asian (SAS)

AF:

0.493

AC:

2377

AN:

4820

European-Finnish (FIN)

AF:

0.404

AC:

4272

AN:

10578

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.330

AC:

22434

AN:

67956

Other (OTH)

AF:

0.338

AC:

713

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1646

3293

4939

6586

8232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.323

Hom.:

39738

Bravo

AF:

0.301

TwinsUK

AF:

0.337

AC:

1251

ALSPAC

AF:

0.334

AC:

1286

ESP6500AA

AF:

0.238

AC:

1050

ESP6500EA

AF:

0.324

AC:

2790

ExAC

AF:

0.348

AC:

42234

Asia WGS

AF:

0.418

AC:

1453

AN:

3478

EpiCase

AF:

0.322

EpiControl

AF:

0.332

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.2

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.096

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.037

MetaRNN

Benign

0.000049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.48

PhyloP100

-0.32

PrimateAI

Benign

0.24

PROVEAN

Benign

0.40

REVEL

Benign

0.067

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MPC

0.068

ClinPred

0.000013

GERP RS

-2.4

PromoterAI

0.0057

Neutral

(source)

Varity_R

0.017

gMVP

0.033

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

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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