rs4942486

chr13-32379251-T-Cchr13-32379251-T-G

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.8755-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,499,332 control chromosomes in the GnomAD database, including 205,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20438 hom., cov: 33)
  • Exomes 𝑓: 0.52 (184643 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:10 O:1
• Conservation: PhyloP100: -1.18

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=-0.88).
• BP6: Variant 13-32379251-T-C is Benign according to our data. Variant chr13-32379251-T-C is described in ClinVar as [Benign]. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in Lovd as [Likely_benign]. Variant chr13-32379251-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8755-66T>C		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8755-66T>C		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78588 AN: 151904 Hom.: 20418 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.522 AC: 703288 AN: 1347310 Hom.: 184643 AF XY: 0.521 AC XY: 351341 AN XY: 674262

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.474

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.516

GnomAD4 genome AF: 0.517 AC: 78659 AN: 152022 Hom.: 20438 Cov.: 33 AF XY: 0.521 AC XY: 38727 AN XY: 74302

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.498

Alfa AF: 0.513 Hom.: 46427

Bravo AF: 0.511

Asia WGS AF: 0.520 AC: 1809 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
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 0.549 (Asian), 0.502 (African), 0.5383 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -

Hereditary cancer-predisposing syndrome Benign:1

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: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	-0.88
Cadd	Benign	0.98
Dann	Benign	0.47

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: rs4942486; hg19: chr13-32953388; COSMIC: COSV66457232; COSMIC: COSV66457232;