17-43094044-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.1487G>A(p.Arg496His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,613,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. R496L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:33O:1

Conservation

PhyloP100: -3.47

Publications

47 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.088642985).

BP6

Variant 17-43094044-C-T is Benign according to our data. Variant chr17-43094044-C-T is described in ClinVar as Benign. ClinVar VariationId is 41805.Status of the report is reviewed_by_expert_panel, 3 stars.

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.1487G>A	p.Arg496His	missense	Exon 10 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.1487G>A	p.Arg496His	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.1487G>A	p.Arg496His	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.1487G>A	p.Arg496His	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.1487G>A	p.Arg496His	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.1487G>A	p.Arg496His	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000446

AC:

112

AN:

251192

AF XY:

0.000486

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000872

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000681

AC:

995

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000663

AC XY:

482

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000853

AC:

948

AN:

1111926

Other (OTH)

AF:

0.000414

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000546

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41394

American (AMR)

AF:

0.000262

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68020

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000686

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

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)

Hereditary cancer-predisposing syndrome (5)

Hereditary breast ovarian cancer syndrome (3)

not provided (3)

BRCA1-related cancer predisposition (1)

Breast and/or ovarian cancer (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.11

CADD

Benign

0.017

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.096

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0039

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.53

PhyloP100

-3.5

PrimateAI

Benign

0.19

PROVEAN

Benign

0.12

REVEL

Uncertain

0.55

Sift

Benign

0.83

Sift4G

Benign

0.76

Polyphen

0.0010

Vest4

0.20

MVP

0.23

MPC

0.10

ClinPred

0.0073

GERP RS

-8.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.013

gMVP

0.057

Mutation Taster

=93/7

polymorphism

(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