17-43044804-CTTTTTTTTTTT-CTTTTTTT

Variant names:

• chr17-43044804-CTTTT-C
• rs59541324
• ENST00000468300.5:c.*976_*979delAAAA

Variant summary

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

The NM_007294.4(BRCA1):​c.*870_*873delAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 368,452 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 0.000058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446
• Publications: 3 publications found

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

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*870_*873delAAAA		3_prime_UTR_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.*870_*873delAAAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000577 AC: 7 AN: 121382 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000676

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0337 AC: 1666 AN: 49390 AF XY: 0.0347

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0330

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0114 AC: 2810 AN: 247058 Hom.: 0 AF XY: 0.0117 AC XY: 1636 AN XY: 140132

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

African (AFR) AF: 0.00745 AC: 43 AN: 5772

American (AMR) AF: 0.0126 AC: 192 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 215 AN: 8798

East Asian (EAS) AF: 0.0172 AC: 202 AN: 11758

South Asian (SAS) AF: 0.0112 AC: 505 AN: 44998

European-Finnish (FIN) AF: 0.00862 AC: 82 AN: 9514

Middle Eastern (MID) AF: 0.0152 AC: 13 AN: 858

European-Non Finnish (NFE) AF: 0.0103 AC: 1423 AN: 138058

Other (OTH) AF: 0.0112 AC: 135 AN: 12010

⚠️ 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.

GnomAD4 genome AF: 0.0000577 AC: 7 AN: 121394 Hom.: 0 Cov.: 0 AF XY: 0.0000523 AC XY: 3 AN XY: 57348

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

African (AFR) AF: 0.00 AC: 0 AN: 31662

American (AMR) AF: 0.00 AC: 0 AN: 11632

Ashkenazi Jewish (ASJ) AF: 0.000327 AC: 1 AN: 3062

East Asian (EAS) AF: 0.00 AC: 0 AN: 4418

South Asian (SAS) AF: 0.00 AC: 0 AN: 3582

European-Finnish (FIN) AF: 0.000386 AC: 2 AN: 5188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.0000676 AC: 4 AN: 59146

Other (OTH) AF: 0.00 AC: 0 AN: 1644

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45

Splicing

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

Other links and lift over

dbSNP: rs59541324; hg19: chr17-41196821;