NM_007294.4:c.1067A>G

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.1067A>G(p.Gln356Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,048 control chromosomes in the GnomAD database, including 2,838 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. Q356W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.046 ( 213 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2625 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:43O:1

Conservation

PhyloP100: 2.37

Publications

221 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=0.0026477277).

BP6

Variant 17-43094464-T-C is Benign according to our data. Variant chr17-43094464-T-C is described in ClinVar as Benign. ClinVar VariationId is 41803.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0639 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.1067A>G	p.Gln356Arg	missense	Exon 10 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.1067A>G	p.Gln356Arg	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.1067A>G	p.Gln356Arg	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.1067A>G	p.Gln356Arg	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.1067A>G	p.Gln356Arg	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.1067A>G	p.Gln356Arg	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0456

AC:

6942

AN:

152212

Hom.:

212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0400

Gnomad ASJ

AF:

0.0833

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0843

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0655

Gnomad OTH

AF:

0.0545

GnomAD2 exomes

AF:

0.0465

AC:

11681

AN:

251138

AF XY:

0.0471

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.0761

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0811

Gnomad NFE exome

AF:

0.0648

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0560

AC:

81929

AN:

1461718

Hom.:

2625

Cov.:

AF XY:

0.0554

AC XY:

40297

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00887

AC:

297

AN:

33480

American (AMR)

AF:

0.0273

AC:

1219

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0779

AC:

2035

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39696

South Asian (SAS)

AF:

0.0136

AC:

1176

AN:

86254

European-Finnish (FIN)

AF:

0.0774

AC:

4121

AN:

53270

Middle Eastern (MID)

AF:

0.0589

AC:

340

AN:

5768

European-Non Finnish (NFE)

AF:

0.0627

AC:

69675

AN:

1112000

Other (OTH)

AF:

0.0507

AC:

3060

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

5090

10180

15269

20359

25449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2450

4900

7350

9800

12250

<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:

0.0456

AC:

6943

AN:

152330

Hom.:

213

Cov.:

AF XY:

0.0453

AC XY:

3371

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0117

AC:

486

AN:

41584

American (AMR)

AF:

0.0399

AC:

611

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0833

AC:

289

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5194

South Asian (SAS)

AF:

0.0128

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0843

AC:

894

AN:

10608

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0655

AC:

4454

AN:

68014

Other (OTH)

AF:

0.0539

AC:

114

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

350

701

1051

1402

1752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0588

Hom.:

1379

Bravo

AF:

0.0413

TwinsUK

AF:

0.0596

AC:

221

ALSPAC

AF:

0.0537

AC:

207

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0642

AC:

552

ExAC

AF:

0.0441

AC:

5350

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0725

EpiControl

AF:

0.0693

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (15)

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

Hereditary breast ovarian cancer syndrome (5)

Hereditary cancer-predisposing syndrome (5)

not provided (5)

Breast ductal adenocarcinoma (1)

Familial cancer of breast (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

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Benign

0.025

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.4

PhyloP100

2.4

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.42

Sift

Uncertain

0.014

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.36

MPC

0.43

ClinPred

0.033

GERP RS

3.7

Varity_R

0.12

gMVP

0.043

Mutation Taster

=97/3

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