rs9595456

Positions:

• chr13-32394606-G-A
• chr13-32394606-G-C
• chr13-32394606-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.9257-83G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,473,682 control chromosomes in the GnomAD database, including 757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.041 (350 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (407 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: -0.949

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=-0.77).
• BP6: Variant 13-32394606-G-A is Benign according to our data. Variant chr13-32394606-G-A is described in ClinVar as [Benign]. Clinvar id is 126207.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394606-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9257-83G>A		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9257-83G>A		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6156 AN: 152114 Hom.: 346 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.0350

GnomAD4 exome AF: 0.00747 AC: 9876 AN: 1321450 Hom.: 407 AF XY: 0.00681 AC XY: 4496 AN XY: 659880

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0769

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0212

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.00690

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0405 AC: 6169 AN: 152232 Hom.: 350 Cov.: 33 AF XY: 0.0405 AC XY: 3012 AN XY: 74434

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0233

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0237 Hom.: 22

Bravo AF: 0.0498

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 0.02972 (Asian), 0.1463 (African), derived from 1000 genomes (2012-04-30). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 17, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:2

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.8
DANN	Benign	0.69

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: rs9595456; hg19: chr13-32968743;