rs80358092

Positions:

• chr17-43049088-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007294.4(BRCA1):​c.5406+33A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,594,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: -0.0500

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-43049088-T-A is Benign according to our data. Variant chr17-43049088-T-A is described in ClinVar as [Benign]. Clinvar id is 55561.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43049088-T-A is described in Lovd as [Benign]. Variant chr17-43049088-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000342 (52/152152) while in subpopulation EAS AF= 0.00966 (50/5174). AF 95% confidence interval is 0.00753. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5406+33A>T		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5406+33A>T		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00964

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000771 AC: 193 AN: 250382 Hom.: 1 AF XY: 0.000806 AC XY: 109 AN XY: 135310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00915

Gnomad SAS exome AF: 0.000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000275 AC: 396 AN: 1442120 Hom.: 0 Cov.: 30 AF XY: 0.000294 AC XY: 211 AN XY: 718616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00776

Gnomad4 SAS exome AF: 0.000537

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000914

Gnomad4 OTH exome AF: 0.000519

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.000403 AC XY: 30 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00966

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000495

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:3

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 0.01224 (Asian), derived from 1000 genomes (2012-04-30). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.9% (79/8420) East Asian chromosomes, 1 homozygote; ClinVar: 1 VUS, 1 LB -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2020	This variant is associated with the following publications: (PMID: 15168169, 18512148, 20104584, 24667779, 8595420, 22505045, 26332594) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 c.5406+33A>T variant was identified in ClinVar (Benign, reviewed by expert panel. Classified as B by ENIGMA, Invitae, LMM Partners HealthCare, Color, ARUP laboratories. Classified as LB by COGR, Counsyl. VUS by BIC) and dbSNP (rs80358092). The BRCA1 c.5406+33A>T variant was identified in control databases in 206 of 281744 chromosomes (1 homozygous) at a frequency of 0.0007312, and was observed at the highest frequency in the East Asian population in 181 of 19914 chromosomes (freq: 0.009089) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant occurs outside of the splicing consensus sequence at a nucleotide that is not conserved in mammals, and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.56

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: rs80358092; hg19: chr17-41201105; COSMIC: COSV58799373;