rs8176259

chr17-43063788-CA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007294.4(BRCA1):c.5152+85del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,110,850 control chromosomes in the GnomAD database, including 235 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.024 (153 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (82 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 17-43063788-CA-C is Benign according to our data. Variant chr17-43063788-CA-C is described in ClinVar as [Benign]. Clinvar id is 125782.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063788-CA-C is described in Lovd as [Benign]. Variant chr17-43063788-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5152+85del		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5152+85del		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 152064 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00255 AC: 2449 AN: 958668 Hom.: 82 AF XY: 0.00213 AC XY: 1050 AN XY: 493306

Gnomad4 AFR exome AF: 0.0839

Gnomad4 AMR exome AF: 0.00366

Gnomad4 ASJ exome AF: 0.000177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00539

GnomAD4 genome AF: 0.0239 AC: 3642 AN: 152182 Hom.: 153 Cov.: 32 AF XY: 0.0230 AC XY: 1711 AN XY: 74384

Gnomad4 AFR AF: 0.0842

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0178 Hom.: 5

Bravo AF: 0.0270

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 17, 2010	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1 (African), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176259; hg19: chr17-41215805;