17-43044804-CTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr17-43044804-C-CTT
• rs59541324
• ENST00000468300.5:c.*978_*979dupAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_007294.4(BRCA1):​c.*872_*873dupAA variant causes a 3 prime UTR 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 0.00058 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*872_*873dupAA		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.*872_*873dupAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000577 AC: 70 AN: 121400 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000172

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000556

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00123 AC: 318 AN: 259290 Hom.: 0 Cov.: 0 AF XY: 0.00110 AC XY: 162 AN XY: 147248

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

African (AFR) AF: 0.00965 AC: 57 AN: 5908

American (AMR) AF: 0.00377 AC: 60 AN: 15920

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 12 AN: 9156

East Asian (EAS) AF: 0.00203 AC: 25 AN: 12308

South Asian (SAS) AF: 0.000519 AC: 25 AN: 48156

European-Finnish (FIN) AF: 0.000501 AC: 5 AN: 9978

Middle Eastern (MID) AF: 0.00214 AC: 2 AN: 936

European-Non Finnish (NFE) AF: 0.000797 AC: 115 AN: 144364

Other (OTH) AF: 0.00135 AC: 17 AN: 12564

⚠️ 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: 0.000577 AC: 70 AN: 121412 Hom.: 2 Cov.: 0 AF XY: 0.000558 AC XY: 32 AN XY: 57358

African (AFR) AF: 0.00183 AC: 58 AN: 31658

American (AMR) AF: 0.000172 AC: 2 AN: 11634

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

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

South Asian (SAS) AF: 0.000558 AC: 2 AN: 3582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5190

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

European-Non Finnish (NFE) AF: 0.000118 AC: 7 AN: 59164

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

Alfa AF: 0.00 Hom.: 100

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;