rs1799943

Positions:

• chr13-32316435-G-A
• chr13-32316435-G-C
• chr13-32316435-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.-26G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,601,606 control chromosomes in the GnomAD database, including 55,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3886 hom., cov: 33)
  • Exomes 𝑓: 0.26 (51773 hom.)
• Consequence: BRCA2 NM_000059.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:24 O:1
• Conservation: PhyloP100: 0.546

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-32316435-G-A is Benign according to our data. Variant chr13-32316435-G-A is described in ClinVar as [Benign]. Clinvar id is 125965.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32316435-G-A is described in Lovd as [Likely_benign]. Variant chr13-32316435-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.-26G>A		5_prime_UTR_variant	2/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.-26G>A		5_prime_UTR_variant	2/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32462 AN: 152032 Hom.: 3894 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.246 AC: 61394 AN: 250044 Hom.: 7996 AF XY: 0.251 AC XY: 33947 AN XY: 135172

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.375

Gnomad SAS exome AF: 0.285

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.262 AC: 379895 AN: 1449454 Hom.: 51773 Cov.: 30 AF XY: 0.264 AC XY: 190683 AN XY: 721840

Gnomad4 AFR exome AF: 0.0975

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.265

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.213 AC: 32439 AN: 152152 Hom.: 3886 Cov.: 33 AF XY: 0.212 AC XY: 15766 AN XY: 74374

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.225

Alfa AF: 0.258 Hom.: 11049

Bravo AF: 0.207

Asia WGS AF: 0.255 AC: 889 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:10

Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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 0.3689 (Asian), 0.04878 (African), 0.2282 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 17, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 27, 2020	- -
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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32398771, 17945002, 23249957, 20352487, 22513257, 16760289) -
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	Color Diagnostics, LLC DBA Color Health	Mar 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 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. -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Fanconi anemia complementation group D1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

Genomic Research Center, Shahid Beheshti University of Medical Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.8
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1799943; hg19: chr13-32890572; COSMIC: COSV61525225; COSMIC: COSV61525225;