17-43104083-AAAGAAGAAG-AAAGAAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_007294.4(BRCA1):c.441+36_441+38delCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,115,902 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 16 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.583

Publications

6 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 17-43104083-AAAG-A is Benign according to our data. Variant chr17-43104083-AAAG-A is described in ClinVar as Benign. ClinVar VariationId is 225704.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00177 (128/72166) while in subpopulation SAS AF = 0.0136 (18/1320). AF 95% confidence interval is 0.00881. There are 1 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR 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	Effect	Exon Rank	Protein	UniProt
BRCA1	NM_007294.4	MANE Select	c.441+36_441+38delCTT	intron	N/A	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.441+36_441+38delCTT	intron	N/A	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.441+36_441+38delCTT	intron	N/A	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.441+36_441+38delCTT	intron	N/A	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.441+36_441+38delCTT	intron	N/A	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.441+36_441+38delCTT	intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

128

AN:

72106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00268

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00216

GnomAD2 exomes

AF:

0.00865

AC:

1657

AN:

191546

AF XY:

0.00829

show subpopulations

Gnomad AFR exome

AF:

0.00607

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.00466

Gnomad FIN exome

AF:

0.0329

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00775

GnomAD4 exome

AF:

0.00192

AC:

2002

AN:

1043736

Hom.:

AF XY:

0.00205

AC XY:

1025

AN XY:

500924

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

24264

American (AMR)

AF:

0.00175

AC:

AN:

18858

Ashkenazi Jewish (ASJ)

AF:

0.000550

AC:

AN:

12726

East Asian (EAS)

AF:

0.00177

AC:

AN:

18044

South Asian (SAS)

AF:

0.0113

AC:

364

AN:

32336

European-Finnish (FIN)

AF:

0.00984

AC:

182

AN:

18494

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

3128

European-Non Finnish (NFE)

AF:

0.00136

AC:

1191

AN:

876156

Other (OTH)

AF:

0.00332

AC:

132

AN:

39730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.00177

AC:

128

AN:

72166

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

34618

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

24590

American (AMR)

AF:

0.00174

AC:

AN:

6916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1396

East Asian (EAS)

AF:

0.000968

AC:

AN:

2066

South Asian (SAS)

AF:

0.0136

AC:

AN:

1320

European-Finnish (FIN)

AF:

0.00268

AC:

AN:

3736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.00111

AC:

AN:

30622

Other (OTH)

AF:

0.00216

AC:

AN:

928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Breast-ovarian cancer, familial, susceptibility to, 1 (2)

Breast and/or ovarian cancer (1)

Familial cancer of breast (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.58

Mutation Taster

=100/0

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