Genetic Variant BRCA1:c.441+33_441+38delCTTCTT (chr17-43104083-AAAGAAG-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_007294.4(BRCA1):c.441+33_441+38delCTTCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,124,644 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.698

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):

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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
BRCA1	NM_007294.4	MANE Select	c.441+33_441+38delCTTCTT	intron	N/A	NP_009225.1
BRCA1	NM_001407581.1		c.441+33_441+38delCTTCTT	intron	N/A	NP_001394510.1
BRCA1	NM_001407582.1		c.441+33_441+38delCTTCTT	intron	N/A	NP_001394511.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.441+33_441+38delCTTCTT	intron	N/A	ENSP00000350283.3
BRCA1	ENST00000471181.7	TSL:1	c.441+33_441+38delCTTCTT	intron	N/A	ENSP00000418960.2
BRCA1	ENST00000470026.6	TSL:1	c.441+33_441+38delCTTCTT	intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes

AF:

0.000166

AC:

AN:

72152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000815

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000145

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000483

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000261

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000313

AC:

AN:

191546

AF XY:

0.0000194

show subpopulations

Gnomad AFR exome

AF:

0.0000731

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000706

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000694

AC:

AN:

1052492

Hom.:

AF XY:

0.0000673

AC XY:

AN XY:

505098

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

24564

American (AMR)

AF:

0.00

AC:

AN:

19026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12856

East Asian (EAS)

AF:

0.00

AC:

AN:

18230

South Asian (SAS)

AF:

0.0000307

AC:

AN:

32522

European-Finnish (FIN)

AF:

0.0000532

AC:

AN:

18792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3170

European-Non Finnish (NFE)

AF:

0.0000759

AC:

AN:

883244

Other (OTH)

AF:

0.0000249

AC:

AN:

40088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000166

AC:

AN:

72152

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

34568

show subpopulations

African (AFR)

AF:

0.0000815

AC:

AN:

24542

American (AMR)

AF:

0.000145

AC:

AN:

6916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1398

East Asian (EAS)

AF:

0.000483

AC:

AN:

2070

South Asian (SAS)

AF:

0.00

AC:

AN:

1318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.000261

AC:

AN:

30636

Other (OTH)

AF:

0.00

AC:

AN:

928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.70

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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