17-43091173-T-G

Position:

• chr17-43091173-T-G

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.4097-141A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 942,952 control chromosomes in the GnomAD database, including 72,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17270 hom., cov: 32)
  • Exomes 𝑓: 0.36 (55698 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:6 O:1
• Conservation: PhyloP100: -2.60

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=-0.95).
• BP6: Variant 17-43091173-T-G is Benign according to our data. Variant chr17-43091173-T-G is described in ClinVar as [Benign]. Clinvar id is 125674.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091173-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4097-141A>C		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4097-141A>C		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68537 AN: 151926 Hom.: 17223 Cov.: 32

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.364 AC: 287828 AN: 790908 Hom.: 55698 Cov.: 11 AF XY: 0.369 AC XY: 151762 AN XY: 410750

Gnomad4 AFR exome AF: 0.687

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.451 AC: 68641 AN: 152044 Hom.: 17270 Cov.: 32 AF XY: 0.453 AC XY: 33687 AN XY: 74314

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.427

Alfa AF: 0.316 Hom.: 1541

Bravo AF: 0.455

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6 Other:1

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), 0.2846 (African), 0.3681 (European), derived from 1000 genomes (2012-04-30). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Aug 07, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:2

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 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.95
CADD	Benign	0.0020
DANN	Benign	0.47

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: rs799916; hg19: chr17-41243190; COSMIC: COSV58794250; COSMIC: COSV58794250;