rs11571836

Positions:

• chr13-32399302-A-G
• chr13-32399302-A-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.*532A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 196,350 control chromosomes in the GnomAD database, including 4,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3037 hom., cov: 32)
  • Exomes 𝑓: 0.24 (1562 hom.)
• Consequence: BRCA2 NM_000059.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.315

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=-0.88).
• BP6: Variant 13-32399302-A-G is Benign according to our data. Variant chr13-32399302-A-G is described in ClinVar as [Benign]. Clinvar id is 209928.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32399302-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.*532A>G		3_prime_UTR_variant	27/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.*532A>G		3_prime_UTR_variant	27/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.*532A>G		3_prime_UTR_variant	27/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2847A>G		non_coding_transcript_exon_variant	26/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2847A>G		3_prime_UTR_variant	26/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28849 AN: 152008 Hom.: 3039 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.243 AC: 10763 AN: 44224 Hom.: 1562 Cov.: 0 AF XY: 0.246 AC XY: 5042 AN XY: 20482

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.210

GnomAD4 genome AF: 0.190 AC: 28841 AN: 152126 Hom.: 3037 Cov.: 32 AF XY: 0.194 AC XY: 14437 AN XY: 74378

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.204

Alfa AF: 0.210 Hom.: 3510

Bravo AF: 0.182

Asia WGS AF: 0.250 AC: 870 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

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

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 0.3811 (Asian), 0.04675 (African), 0.2177 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	This variant is associated with the following publications: (PMID: 23299404) -

Fanconi anemia complementation group D1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.80

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: rs11571836; hg19: chr13-32973439;