17-43079499-C-T

Position:

• chr17-43079499-C-T

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.4358-2885G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,219,878 control chromosomes in the GnomAD database, including 76,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7934 hom., cov: 32)
  • Exomes 𝑓: 0.36 (68833 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.528

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]

RPL21P4 (HGNC:17959): (ribosomal protein L21 pseudogene 4)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-43079499-C-T is Benign according to our data. Variant chr17-43079499-C-T is described in ClinVar as [Benign]. Clinvar id is 209399.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43079499-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4358-2885G>A		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4358-2885G>A		intron_variant		1	NM_007294.4	P4
RPL21P4	ENST00000497954.1	n.198C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48067 AN: 151880 Hom.: 7928 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.356 AC: 380546 AN: 1067880 Hom.: 68833 Cov.: 16 AF XY: 0.361 AC XY: 198099 AN XY: 549010

Gnomad4 AFR exome AF: 0.241

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.316 AC: 48101 AN: 151998 Hom.: 7934 Cov.: 32 AF XY: 0.323 AC XY: 24016 AN XY: 74308

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.338

Alfa AF: 0.316 Hom.: 961

Bravo AF: 0.302

Asia WGS AF: 0.418 AC: 1453 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	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
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 0.3304 (Asian), 0.2154 (African), 0.3588 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.3
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176193; hg19: chr17-41231516; COSMIC: COSV58789905;