rs1012130

Positions:

• chr13-32395894-T-C
• chr13-32395894-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.9501+961T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 189,324 control chromosomes in the GnomAD database, including 6,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4991 hom., cov: 29)
  • Exomes 𝑓: 0.21 (1245 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.191

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=-0.86).
• BP6: Variant 13-32395894-T-C is Benign according to our data. Variant chr13-32395894-T-C is described in ClinVar as [Benign]. Clinvar id is 209912.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32395894-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9501+961T>C		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9501+961T>C		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37649 AN: 150730 Hom.: 4987 Cov.: 29

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.208 AC: 7992 AN: 38482 Hom.: 1245 AF XY: 0.199 AC XY: 4817 AN XY: 24184

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0547

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.250 AC: 37692 AN: 150842 Hom.: 4991 Cov.: 29 AF XY: 0.248 AC XY: 18228 AN XY: 73614

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.0816

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.231

Alfa AF: 0.247 Hom.: 4690

Bravo AF: 0.250

Asia WGS AF: 0.155 AC: 536 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 0.08392 (Asian), 0.3069 (African), 0.285 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.0
DANN	Benign	0.81

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: rs1012130; hg19: chr13-32970031;