17-43067543-C-T

Position:

• chr17-43067543-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.5074+65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,362,902 control chromosomes in the GnomAD database, including 51,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5015 hom., cov: 30)
  • Exomes 𝑓: 0.27 (46555 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3 O:1
• Conservation: PhyloP100: 0.167

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-43067543-C-T is Benign according to our data. Variant chr17-43067543-C-T is described in ClinVar as [Benign]. Clinvar id is 127126.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067543-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5074+65G>A		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5074+65G>A		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37549 AN: 151896 Hom.: 5009 Cov.: 30

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.270 AC: 327234 AN: 1210886 Hom.: 46555 Cov.: 16 AF XY: 0.277 AC XY: 170284 AN XY: 613718

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.247 AC: 37564 AN: 152016 Hom.: 5015 Cov.: 30 AF XY: 0.254 AC XY: 18862 AN XY: 74296

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.267

Alfa AF: 0.253 Hom.: 1415

Bravo AF: 0.234

Asia WGS AF: 0.390 AC: 1356 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

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)

Jan 12, 2015

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3322 (Asian), 0.1402 (African), 0.2744 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

Genomic Research Center, Shahid Beheshti University of Medical Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.74

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: rs8176235; hg19: chr17-41219560; COSMIC: COSV58786515;