rs8176318

chr17-43045257-C-A

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.*421G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 541,890 control chromosomes in the GnomAD database, including 32,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7189 hom., cov: 32)
  • Exomes 𝑓: 0.35 (24830 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.956

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=-0.82).
• BP6: Variant 17-43045257-C-A is Benign according to our data. Variant chr17-43045257-C-A is described in ClinVar as [Benign]. Clinvar id is 209234.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045257-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.*421G>T		3_prime_UTR_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.*421G>T		3_prime_UTR_variant	23/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44753 AN: 151978 Hom.: 7190 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.315

GnomAD3 exomes AF: 0.338 AC: 44084 AN: 130324 Hom.: 8200 AF XY: 0.354 AC XY: 25172 AN XY: 71152

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.378

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.346 AC: 134910 AN: 389794 Hom.: 24830 Cov.: 0 AF XY: 0.361 AC XY: 76822 AN XY: 212732

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.360

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.389

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.294 AC: 44746 AN: 152096 Hom.: 7189 Cov.: 32 AF XY: 0.300 AC XY: 22306 AN XY: 74312

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.319

Alfa AF: 0.318 Hom.: 9508

Bravo AF: 0.273

Asia WGS AF: 0.402 AC: 1397 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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), 0.126 (African), 0.3588 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneKor MSA

Nov 01, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

This variant is associated with the following publications: (PMID: 24915755, 21191178, 19405875, 29582646) -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	9.8
Dann	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176318; hg19: chr17-41197274;