chr17-43044804-CTT-C

Position:

• chr17-43044804-CTT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_007294.4(BRCA1):​c.*872_*873del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 360,652 control chromosomes in the GnomAD database, including 3,232 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (3150 hom., cov: 0)
  • Exomes 𝑓: 0.28 (82 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.*872_*873del		3_prime_UTR_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.*872_*873del		3_prime_UTR_variant	23/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 33647 AN: 121158 Hom.: 3154 Cov.: 0

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.287 AC: 14161 AN: 49390 Hom.: 63 AF XY: 0.288 AC XY: 7817 AN XY: 27116

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.328

Gnomad SAS exome AF: 0.320

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.279 AC: 66926 AN: 239480 Hom.: 82 AF XY: 0.286 AC XY: 39017 AN XY: 136506

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.278 AC: 33630 AN: 121172 Hom.: 3150 Cov.: 0 AF XY: 0.280 AC XY: 16028 AN XY: 57306

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.300

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;