chr17-43044804-CTTTTT-C

Variant names:

• chr17-43044804-CTTTTT-C
• rs59541324
• ENST00000468300.5:c.*975_*979delAAAAA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The ENST00000468300.5(BRCA1):​c.*975_*979delAAAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 376,204 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: BRCA1 ENST00000468300.5 splice_region
• 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 Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00433 (1102/254792) while in subpopulation MID AF= 0.0144 (13/904). AF 95% confidence interval is 0.00851. There are 0 homozygotes in gnomad4_exome. There are 649 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*869_*873delAAAAA		3_prime_UTR_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654	c.*869_*873delAAAAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 56 AN: 121400 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.000226

Gnomad SAS AF: 0.000556

Gnomad FIN AF: 0.000578

Gnomad MID AF: 0.0280

Gnomad NFE AF: 0.000389

Gnomad OTH AF: 0.00244

GnomAD4 exome AF: 0.00433 AC: 1102 AN: 254792 Hom.: 0 AF XY: 0.00449 AC XY: 649 AN XY: 144578

Gnomad4 AFR exome AF: 0.00253

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.00554

Gnomad4 SAS exome AF: 0.00434

Gnomad4 FIN exome AF: 0.00235

Gnomad4 NFE exome AF: 0.00414

Gnomad4 OTH exome AF: 0.00526

GnomAD4 genome AF: 0.000461 AC: 56 AN: 121412 Hom.: 1 Cov.: 0 AF XY: 0.000540 AC XY: 31 AN XY: 57360

Gnomad4 AFR AF: 0.0000632

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.000327

Gnomad4 EAS AF: 0.000226

Gnomad4 SAS AF: 0.000558

Gnomad4 FIN AF: 0.000578

Gnomad4 NFE AF: 0.000389

Gnomad4 OTH AF: 0.00243

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 11, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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;