Genetic Variant BRCA2:c.-52A>G (chr13-32315655-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.179

Variant links:

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]

BRCA2 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.-52A>G		5_prime_UTR_variant	Exon 1 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152 link	c.-52A>G		5_prime_UTR_variant	Exon 1 of 27	5	NM_000059.4	ENSP00000369497.3		P51587
BRCA2	ENST00000530893 link	c.-417A>G		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000499438.2		A0A590UJI7

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23931

AN:

152030

Hom.:

1995

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.121

AC XY:

AN XY:

show subpopulations

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.:

AF XY:

0.155

AC XY:

11517

AN XY:

74378

show subpopulations

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:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over