chr13-32329548-C-T

Position:

• chr13-32329548-C-T

Variant summary

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

The ENST00000530893.7(BRCA2):​c.312+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,307,266 control chromosomes in the GnomAD database, including 24,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3387 hom., cov: 32)
  • Exomes 𝑓: 0.19 (21607 hom.)
• Consequence: BRCA2 ENST00000530893.7 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -0.265

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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-32329548-C-T is Benign according to our data. Variant chr13-32329548-C-T is described in ClinVar as [Benign]. Clinvar id is 126192.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32329548-C-T is described in Lovd as [Likely_benign]. Variant chr13-32329548-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.681+56C>T		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.681+56C>T		intron_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.312+56C>T		intron_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.681+56C>T		intron_variant		2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31123 AN: 151760 Hom.: 3378 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0824

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.188 AC: 217330 AN: 1155390 Hom.: 21607 AF XY: 0.185 AC XY: 108379 AN XY: 584296

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0576

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.205 AC: 31170 AN: 151876 Hom.: 3387 Cov.: 32 AF XY: 0.204 AC XY: 15168 AN XY: 74230

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0830

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.189

Alfa AF: 0.189 Hom.: 3485

Bravo AF: 0.206

Asia WGS AF: 0.141 AC: 489 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Apr 12, 1999	- -
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 0.07343 (Asian), 0.313 (African), 0.2018 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:4

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, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Hereditary cancer-predisposing syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.80
CADD	Benign	7.0
DANN	Benign	0.63

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: rs2126042; hg19: chr13-32903685; COSMIC: COSV66457755;