rs11571651

Positions:

• chr13-32336214-G-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.1910-51G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,549,260 control chromosomes in the GnomAD database, including 2,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.041 (216 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1841 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.0290

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=-0.82).
• BP6: Variant 13-32336214-G-T is Benign according to our data. Variant chr13-32336214-G-T is described in ClinVar as [Benign]. Clinvar id is 209688.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336214-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1910-51G>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.1910-51G>T		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6210 AN: 152100 Hom.: 213 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0973

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0506 AC: 10617 AN: 209908 Hom.: 423 AF XY: 0.0531 AC XY: 6017 AN XY: 113302

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.0724

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0417 AC: 58223 AN: 1397042 Hom.: 1841 Cov.: 29 AF XY: 0.0441 AC XY: 30615 AN XY: 694330

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0760

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0409 AC: 6229 AN: 152218 Hom.: 216 Cov.: 32 AF XY: 0.0436 AC XY: 3242 AN XY: 74414

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0980

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.0986

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0337 Hom.: 17

Bravo AF: 0.0422

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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 0.1031 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Mar 07, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.53

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: rs11571651; hg19: chr13-32910351;