rs4942448

chr13-32349553-C-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.7007+2657C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 151,842 control chromosomes in the GnomAD database, including 3,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.20 (3334 hom., cov: 29)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.473

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=-0.91).
• BP6: Variant 13-32349553-C-T is Benign according to our data. Variant chr13-32349553-C-T is described in ClinVar as [Benign]. Clinvar id is 209733.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32349553-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7007+2657C>T		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7007+2657C>T		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30847 AN: 151724 Hom.: 3328 Cov.: 29

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.189

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.203 AC: 30887 AN: 151842 Hom.: 3334 Cov.: 29 AF XY: 0.202 AC XY: 15018 AN XY: 74214

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0749

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.188

Alfa AF: 0.208 Hom.: 439

Bravo AF: 0.204

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

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 0.06294 (Asian), 0.3028 (African), 0.2018 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.6
Dann	Benign	0.49

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: rs4942448; hg19: chr13-32923690;