rs799923

Positions:

• chr17-43099914-G-A
• chr17-43099914-G-C
• chr17-43099914-G-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.442-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,516,640 control chromosomes in the GnomAD database, including 35,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2485 hom., cov: 31)
  • Exomes 𝑓: 0.21 (33243 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:15 O:1
• Conservation: PhyloP100: -0.706

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 17-43099914-G-A is Benign according to our data. Variant chr17-43099914-G-A is described in ClinVar as [Benign]. Clinvar id is 125864.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099914-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.442-34C>T		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.442-34C>T		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23922 AN: 152074 Hom.: 2483 Cov.: 31

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.173 AC: 43454 AN: 251154 Hom.: 4578 AF XY: 0.182 AC XY: 24692 AN XY: 135728

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.213 AC: 290248 AN: 1364448 Hom.: 33243 Cov.: 21 AF XY: 0.214 AC XY: 146025 AN XY: 683742

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.0979

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.000485

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.157 AC: 23920 AN: 152192 Hom.: 2485 Cov.: 31 AF XY: 0.154 AC XY: 11463 AN XY: 74408

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.170

Alfa AF: 0.220 Hom.: 6052

Bravo AF: 0.148

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4 Other:1

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 0.0122 (African), 0.219 (European), derived from 1000 genomes (2012-04-30). -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23249957, 27223485, 15564800) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 24, 2020	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.38
DANN	Benign	0.37

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: rs799923; hg19: chr17-41251931; COSMIC: COSV58783441; COSMIC: COSV58783441;