chr17-43044804-CTT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_007294.4(BRCA1):c.*872_*873delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 360,652 control chromosomes in the GnomAD database, including 3,232 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.28 ( 3150 hom., cov: 0)

Exomes 𝑓: 0.28 ( 82 hom. )

Consequence

BRCA1
NM_007294.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.446

Publications

3 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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.872_873delAA		3_prime_UTR_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.872_873delAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

33647

AN:

121158

Hom.:

3154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.247

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.322

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.331

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.287

AC:

14161

AN:

49390

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.279

AC:

66926

AN:

239480

Hom.:

AF XY:

0.286

AC XY:

39017

AN XY:

136506

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.217

AC:

1186

AN:

5474

American (AMR)

AF:

0.211

AC:

3039

AN:

14394

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

2269

AN:

8660

East Asian (EAS)

AF:

0.277

AC:

3138

AN:

11328

South Asian (SAS)

AF:

0.340

AC:

15460

AN:

45506

European-Finnish (FIN)

AF:

0.292

AC:

2688

AN:

9192

Middle Eastern (MID)

AF:

0.282

AC:

245

AN:

870

European-Non Finnish (NFE)

AF:

0.270

AC:

35774

AN:

132510

Other (OTH)

AF:

0.271

AC:

3127

AN:

11546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

3616

7232

10847

14463

18079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

33630

AN:

121172

Hom.:

3150

Cov.:

AF XY:

0.280

AC XY:

16028

AN XY:

57306

show subpopulations

African (AFR)

AF:

0.210

AC:

6638

AN:

31620

American (AMR)

AF:

0.243

AC:

2827

AN:

11632

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1015

AN:

3060

East Asian (EAS)

AF:

0.322

AC:

1414

AN:

4392

South Asian (SAS)

AF:

0.432

AC:

1540

AN:

3562

European-Finnish (FIN)

AF:

0.351

AC:

1822

AN:

5188

Middle Eastern (MID)

AF:

0.329

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.298

AC:

17602

AN:

59018

Other (OTH)

AF:

0.300

AC:

493

AN:

1644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

942

1884

2827

3769

4711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0951

Hom.:

100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.45

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr17-43044804-CTT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over