ENST00000468300.5:c.*979dupA

Variant names:

• chr17-43044804-C-CT
• rs59541324
• ENST00000468300.5:c.*979dupA

Variant summary

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

The ENST00000468300.5(BRCA1):​c.*979dupA variant causes a splice region change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.048 (506 hom., cov: 0)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: BRCA1 ENST00000468300.5 splice_region
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*873dupA		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.*873dupA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 5855 AN: 121380 Hom.: 505 Cov.: 0

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00478

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.000653

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.000578

Gnomad MID AF: 0.00400

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0334 AC: 1649 AN: 49390 AF XY: 0.0305

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0519

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0344

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0204 AC: 5220 AN: 256116 Hom.: 0 Cov.: 0 AF XY: 0.0193 AC XY: 2812 AN XY: 145606

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

African (AFR) AF: 0.108 AC: 611 AN: 5674

American (AMR) AF: 0.0399 AC: 624 AN: 15656

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 126 AN: 9076

East Asian (EAS) AF: 0.0285 AC: 345 AN: 12122

South Asian (SAS) AF: 0.0114 AC: 542 AN: 47710

European-Finnish (FIN) AF: 0.0132 AC: 130 AN: 9844

Middle Eastern (MID) AF: 0.0130 AC: 12 AN: 926

European-Non Finnish (NFE) AF: 0.0180 AC: 2562 AN: 142710

Other (OTH) AF: 0.0216 AC: 268 AN: 12398

⚠️ 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: 0.0483 AC: 5863 AN: 121390 Hom.: 506 Cov.: 0 AF XY: 0.0480 AC XY: 2756 AN XY: 57358

African (AFR) AF: 0.170 AC: 5381 AN: 31636

American (AMR) AF: 0.0179 AC: 208 AN: 11632

Ashkenazi Jewish (ASJ) AF: 0.000653 AC: 2 AN: 3062

East Asian (EAS) AF: 0.00385 AC: 17 AN: 4418

South Asian (SAS) AF: 0.00112 AC: 4 AN: 3582

European-Finnish (FIN) AF: 0.000578 AC: 3 AN: 5188

Middle Eastern (MID) AF: 0.00446 AC: 1 AN: 224

European-Non Finnish (NFE) AF: 0.00331 AC: 196 AN: 59168

Other (OTH) AF: 0.0286 AC: 47 AN: 1644

Alfa AF: 0.00437 Hom.: 100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=98/2	polymorphism (auto)

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;