rs8176233

Positions:

• chr17-43067787-T-C
• chr17-43067787-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.4987-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 974,970 control chromosomes in the GnomAD database, including 56,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7679 hom., cov: 27)
  • Exomes 𝑓: 0.33 (48337 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:9 O:1
• Conservation: PhyloP100: -2.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 17-43067787-T-C is Benign according to our data. Variant chr17-43067787-T-C is described in ClinVar as [Benign]. Clinvar id is 125749.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067787-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4987-92A>G		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4987-92A>G		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.314 AC: 46858 AN: 149172 Hom.: 7674 Cov.: 27

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.334 AC: 276116 AN: 825700 Hom.: 48337 AF XY: 0.343 AC XY: 148714 AN XY: 433944

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.494

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.314 AC: 46888 AN: 149270 Hom.: 7679 Cov.: 27 AF XY: 0.319 AC XY: 23141 AN XY: 72518

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.336

Alfa AF: 0.325 Hom.: 1922

Bravo AF: 0.303

Asia WGS AF: 0.415 AC: 1443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3 Other:1

not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
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 0.3322 (Asian), 0.2175 (African), 0.3615 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.20
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8176233; hg19: chr17-41219804; COSMIC: COSV58794208;