17-43044804-CTTTTT-C

Variant names:

• chr17-43044804-CTTTTT-C
• rs59541324
• ENST00000468300.5:c.*975_*979delAAAAA

Variant summary

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

The NM_007294.4(BRCA1):​c.*869_*873delAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 376,204 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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.*869_*873delAAAAA		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.*869_*873delAAAAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 56 AN: 121400 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.000226

Gnomad SAS AF: 0.000556

Gnomad FIN AF: 0.000578

Gnomad MID AF: 0.0280

Gnomad NFE AF: 0.000389

Gnomad OTH AF: 0.00244

GnomAD4 exome AF: 0.00433 AC: 1102 AN: 254792 Hom.: 0 AF XY: 0.00449 AC XY: 649 AN XY: 144578

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

African (AFR) AF: 0.00253 AC: 15 AN: 5928

American (AMR) AF: 0.00279 AC: 44 AN: 15746

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 83 AN: 9004

East Asian (EAS) AF: 0.00554 AC: 67 AN: 12094

South Asian (SAS) AF: 0.00434 AC: 204 AN: 46986

European-Finnish (FIN) AF: 0.00235 AC: 23 AN: 9798

Middle Eastern (MID) AF: 0.0144 AC: 13 AN: 904

European-Non Finnish (NFE) AF: 0.00414 AC: 588 AN: 141986

Other (OTH) AF: 0.00526 AC: 65 AN: 12346

⚠️ 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: 0.000461 AC: 56 AN: 121412 Hom.: 1 Cov.: 0 AF XY: 0.000540 AC XY: 31 AN XY: 57360

African (AFR) AF: 0.0000632 AC: 2 AN: 31662

American (AMR) AF: 0.00112 AC: 13 AN: 11634

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

East Asian (EAS) AF: 0.000226 AC: 1 AN: 4420

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

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

Middle Eastern (MID) AF: 0.0313 AC: 7 AN: 224

European-Non Finnish (NFE) AF: 0.000389 AC: 23 AN: 59160

Other (OTH) AF: 0.00243 AC: 4 AN: 1644

Alfa AF: 0.00 Hom.: 100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 11, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=93/7	polymorphism

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;