rs206070

Positions:

• chr13-32322709-G-A
• chr13-32322709-G-C

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.317-2367G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,188 control chromosomes in the GnomAD database, including 1,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.13 (1644 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.252

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=-0.48).
• BP6: Variant 13-32322709-G-A is Benign according to our data. Variant chr13-32322709-G-A is described in ClinVar as [Benign]. Clinvar id is 209635.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32322709-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.317-2367G>A		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.317-2367G>A		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19864 AN: 152070 Hom.: 1646 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.130 AC: 19854 AN: 152188 Hom.: 1644 Cov.: 32 AF XY: 0.128 AC XY: 9552 AN XY: 74392

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.141

Alfa AF: 0.166 Hom.: 2108

Bravo AF: 0.122

Asia WGS AF: 0.0870 AC: 304 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 0.1503 (Asian), 0.01016 (African), 0.1781 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.96

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: rs206070; hg19: chr13-32896846;