chr17-43044804-CTTTTT-C

Position:

• chr17-43044804-CTTTTT-C

Variant summary

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

The NM_007294.4(BRCA1):​c.*869_*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 0.00308 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 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 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/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*869_*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.*869_*873del		3_prime_UTR_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

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;