rs8176234

Positions:

• chr17-43067763-T-C

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.4987-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,221,538 control chromosomes in the GnomAD database, including 72,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7830 hom., cov: 28)
  • Exomes 𝑓: 0.34 (64661 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: -2.25

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=-0.91).
• BP6: Variant 17-43067763-T-C is Benign according to our data. Variant chr17-43067763-T-C is described in ClinVar as [Benign]. Clinvar id is 125746.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067763-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4987-68A>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.4987-68A>G		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47653 AN: 151000 Hom.: 7826 Cov.: 28

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.342 AC: 365744 AN: 1070422 Hom.: 64661 AF XY: 0.348 AC XY: 191143 AN XY: 549356

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.497

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.340

GnomAD4 genome AF: 0.316 AC: 47682 AN: 151116 Hom.: 7830 Cov.: 28 AF XY: 0.321 AC XY: 23667 AN XY: 73714

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.337

Alfa AF: 0.317 Hom.: 971

Bravo AF: 0.303

Asia WGS AF: 0.416 AC: 1445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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). -

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 cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 11, 2014

- -

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	-0.91
CADD	Benign	0.55
DANN	Benign	0.41

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: rs8176234; hg19: chr17-41219780; COSMIC: COSV58794203;