rs138193280

chr13-32341273-CAATT-Cchr13-32341273-C-CAATT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000059.4(BRCA2):c.6841+80_6841+83del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,594,908 control chromosomes in the GnomAD database, including 74,988 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6125 hom., cov: 19)
  • Exomes 𝑓: 0.31 (68863 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:2 B:7 O:1
• Conservation: PhyloP100: 0.759

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 -16 ACMG points.

• BP6: Variant 13-32341273-CAATT-C is Benign according to our data. Variant chr13-32341273-CAATT-C is described in ClinVar as [Benign]. Clinvar id is 126122.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32341273-CAATT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6841+80_6841+83del		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6841+80_6841+83del		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42671 AN: 151646 Hom.: 6128 Cov.: 19

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.306 AC: 441481 AN: 1443142 Hom.: 68863 AF XY: 0.307 AC XY: 220348 AN XY: 718630

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.281 AC: 42663 AN: 151766 Hom.: 6125 Cov.: 19 AF XY: 0.282 AC XY: 20942 AN XY: 74156

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.271

Alfa AF: 0.174 Hom.: 378

Bravo AF: 0.272

Asia WGS AF: 0.278 AC: 968 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 17, 2010	- -
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 0.38 (Asian), 0.18 (African), 0.29 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 10, 2015

- -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

Genomic Research Center, Shahid Beheshti University of Medical Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs11571661; hg19: chr13-32915410;