rs273900734

chr17-43074584-G-C

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.4485-63C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,458,920 control chromosomes in the GnomAD database, including 85,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7942 hom., cov: 32)
  • Exomes 𝑓: 0.34 (77372 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:2 B:6
• Conservation: PhyloP100: 0.00200

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=-0.92).
• BP6: Variant 17-43074584-G-C is Benign according to our data. Variant chr17-43074584-G-C is described in ClinVar as [Benign]. Clinvar id is 209374.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074584-G-C 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.4485-63C>G		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4485-63C>G		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48100 AN: 151960 Hom.: 7936 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.341 AC: 445206 AN: 1306842 Hom.: 77372 AF XY: 0.346 AC XY: 226754 AN XY: 655564

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.317 AC: 48134 AN: 152078 Hom.: 7942 Cov.: 32 AF XY: 0.323 AC XY: 24018 AN XY: 74336

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.337

Alfa AF: 0.316 Hom.: 967

Bravo AF: 0.302

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:2

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). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 22, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.7
Dann	Benign	0.60

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: rs273900734; hg19: chr17-41226601; COSMIC: COSV58794229; COSMIC: COSV58794229;