rs8176258

chr17-43064004-G-Achr17-43064004-G-Cchr17-43064004-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(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 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: -0.152

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=-0.81).
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5075-53C>T		intron_variant		ENST00000357654.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2848 AN: 152150 Hom.: 42 Cov.: 32

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

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.: 42 Cov.: 32 AF XY: 0.0186 AC XY: 1387 AN XY: 74450

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.: 18

Bravo AF: 0.0170

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign: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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Benign:2

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

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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) “With Uncertain significance allele”, 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

Other links and lift over

dbSNP: rs8176258; hg19: chr17-41216021; COSMIC: COSV58789845; COSMIC: COSV58789845;