rs8176258

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000357654.9(BRCA1):c.5075-53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,533,560 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.019 ( 42 hom., cov: 32)

Exomes 𝑓: 0.024 ( 493 hom. )

Consequence

BRCA1
ENST00000357654.9 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: -0.152

Variant links:

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]

BRCA1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 17-43064004-G-A is Benign according to our data. Variant chr17-43064004-G-A is described in ClinVar as [Benign]. Clinvar id is 125760.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43064004-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2848/152268) while in subpopulation NFE AF= 0.0273 (1854/68008). AF 95% confidence interval is 0.0262. There are 42 homozygotes in gnomad4. There are 1387 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5075-53C>T		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5075-53C>T		intron_variant		1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2848

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00785

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0143

GnomAD4 exome

AF:

0.0238

AC:

32886

AN:

1381292

Hom.:

493

AF XY:

0.0232

AC XY:

16024

AN XY:

691340

show subpopulations

Gnomad4 AFR exome

AF:

0.00369

Gnomad4 AMR exome

AF:

0.0125

Gnomad4 ASJ exome

AF:

0.0196

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.0116

Gnomad4 FIN exome

AF:

0.0321

Gnomad4 NFE exome

AF:

0.0267

Gnomad4 OTH exome

AF:

0.0208

GnomAD4 genome

AF:

0.0187

AC:

2848

AN:

152268

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1387

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00407

Gnomad4 AMR

AF:

0.0205

Gnomad4 ASJ

AF:

0.0136

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00786

Gnomad4 FIN

AF:

0.0347

Gnomad4 NFE

AF:

0.0273

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0189

Hom.:

Bravo

AF:

0.0170

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:4

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 0.03166 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:2

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	-	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Nov 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2015	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 c.5075-53C>T variant is not expected to have clinical significance as it occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in 2 of 148 proband chromosomes (frequency: 0.027) from individuals or families with breast cancer and was present in 2 of 480 control chromosomes (frequency: 0.0.004) from healthy individuals (Cvok 2008, Jara 2006, Pietschmann 2005). This variant was identified in several populations at polymorphic frequencies, including: the 1000 Genomes Project (frequency: 0.015), HAPMAP-CEU (frequency: 0.034), HAP-YRI (frequency: 0.031), and the European American population of the ESP Project (frequency: 0.02). The variant was also listed in dbSNP (ID: rs8176258) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, the ClinVar database, the BIC database (20X with no clinical importance and categorized as Class 1: Not pathogenic/low clinical significance), and in UMD (209X as a neutral variant). In the UMD database, the variant was identified with 12 different co-occurring pathogenic BRCA1 variants and 11 different co-occurring pathogenic BRCA2 variants, increasing the likelihood that the c.5075-53C>T variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.1

DANN

Benign

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over