chr17-43044804-CT-C

Position:

• chr17-43044804-CT-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.*873del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1131 hom., cov: 0)
  • Exomes 𝑓: 0.18 (21 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.446

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 17-43044804-CT-C is Benign according to our data. Variant chr17-43044804-CT-C is described in ClinVar as [Benign]. Clinvar id is 264856.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43044804-CT-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*873del		3_prime_UTR_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.*873del		3_prime_UTR_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23344 AN: 121312 Hom.: 1131 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.187 AC: 9224 AN: 49390 Hom.: 22 AF XY: 0.184 AC XY: 4979 AN XY: 27116

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.178 AC: 44598 AN: 250200 Hom.: 21 Cov.: 0 AF XY: 0.177 AC XY: 25187 AN XY: 142054

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.192 AC: 23340 AN: 121322 Hom.: 1131 Cov.: 0 AF XY: 0.188 AC XY: 10802 AN XY: 57358

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.196

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

Benign, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Sep 28, 2016

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.5358 (European), 0.4924 (African), 0.464 (Admixed American/Latino), 0.4583 (East Asian), 0.5521 (South Asian), derived from 1000 genomes (2013-05-02). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59541324; hg19: chr17-41196821;