17-43125170-G-C

Position:

• chr17-43125170-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000357654.9(BRCA1):​c.-20+101C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 443,588 control chromosomes in the GnomAD database, including 46,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20395 hom., cov: 22)
  • Exomes 𝑓: 0.40 (26073 hom.)
• Consequence: BRCA1 ENST00000357654.9 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.23

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=-0.88).
• BP6: Variant 17-43125170-G-C is Benign according to our data. Variant chr17-43125170-G-C is described in ClinVar as [Benign]. Clinvar id is 189123.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43125170-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.-20+101C>G		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.-20+101C>G		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.505 AC: 71352 AN: 141246 Hom.: 20340 Cov.: 22

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.482

GnomAD3 exomes AF: 0.410 AC: 52592 AN: 128296 Hom.: 11705 AF XY: 0.413 AC XY: 29026 AN XY: 70268

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.381

Gnomad SAS exome AF: 0.529

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.401 AC: 121234 AN: 302240 Hom.: 26073 Cov.: 0 AF XY: 0.410 AC XY: 70563 AN XY: 172198

Gnomad4 AFR exome AF: 0.820

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.528

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.506 AC: 71461 AN: 141348 Hom.: 20395 Cov.: 22 AF XY: 0.509 AC XY: 34702 AN XY: 68192

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.538

Gnomad4 FIN AF: 0.440

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.486

Alfa AF: 0.298 Hom.: 1164

Bravo AF: 0.498

Asia WGS AF: 0.472 AC: 1642 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	literature only	Counsyl	Jan 13, 2015	- -
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), 0.1362 (African), 0.3694 (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	Jun 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneKor MSA

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.96
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs799905; hg19: chr17-41277187; COSMIC: COSV58786469; COSMIC: COSV58786469;