17-43082287-C-T

Position:

• chr17-43082287-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.4357+117G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 1,141,584 control chromosomes in the GnomAD database, including 4,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.070 (452 hom., cov: 32)
  • Exomes 𝑓: 0.082 (3680 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: -0.445

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=-0.85).
• BP6: Variant 17-43082287-C-T is Benign according to our data. Variant chr17-43082287-C-T is described in ClinVar as [Benign]. Clinvar id is 125708.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082287-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4357+117G>A		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4357+117G>A		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10731 AN: 152132 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0917

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.0733

GnomAD4 exome AF: 0.0824 AC: 81503 AN: 989334 Hom.: 3680 AF XY: 0.0836 AC XY: 41808 AN XY: 500118

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.0359

Gnomad4 ASJ exome AF: 0.0891

Gnomad4 EAS exome AF: 0.0991

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.0809

Gnomad4 OTH exome AF: 0.0774

GnomAD4 genome AF: 0.0705 AC: 10728 AN: 152250 Hom.: 452 Cov.: 32 AF XY: 0.0720 AC XY: 5359 AN XY: 74426

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.0968

Gnomad4 EAS AF: 0.0919

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.0872

Gnomad4 OTH AF: 0.0726

Alfa AF: 0.0798 Hom.: 711

Bravo AF: 0.0602

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Aug 07, 2009	- -
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 0.08566 (Asian), 0.03862 (African), 0.07916 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.49
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: rs3737559; hg19: chr17-41234304; COSMIC: COSV58789590; COSMIC: COSV58789590;