13-32315655-A-G

Position:

• chr13-32315655-A-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.-52A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,242 control chromosomes in the GnomAD database, including 1,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1995 hom., cov: 33)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: BRCA2 NM_000059.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.179

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=-0.79).
• BP6: Variant 13-32315655-A-G is Benign according to our data. Variant chr13-32315655-A-G is described in ClinVar as [Benign]. Clinvar id is 209600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32315655-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.-52A>G		5_prime_UTR_variant	1/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.-52A>G		5_prime_UTR_variant	1/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23931 AN: 152030 Hom.: 1995 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.117 AC: 11 AN: 94 Hom.: 1 Cov.: 0 AF XY: 0.121 AC XY: 7 AN XY: 58

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.157 AC: 23932 AN: 152148 Hom.: 1995 Cov.: 33 AF XY: 0.155 AC XY: 11517 AN XY: 74378

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.176

Alfa AF: 0.136 Hom.: 649

Bravo AF: 0.161

Asia WGS AF: 0.120 AC: 417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 0.1836 (Asian), 0.126 (African), 0.1636 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneKor MSA

Nov 01, 2017

- -

Fanconi anemia complementation group D1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.0
DANN	Benign	0.68

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: rs206118; hg19: chr13-32889792;