chr13-32399139-A-G

Position:

• chr13-32399139-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.*369A>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 0.247 in 231,366 control chromosomes in the GnomAD database, including 7,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5789 hom., cov: 30)
  • Exomes 𝑓: 0.20 (2181 hom.)
• Consequence: BRCA2 NM_000059.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.0450

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 13-32399139-A-G is Benign according to our data. Variant chr13-32399139-A-G is described in ClinVar as [Benign]. Clinvar id is 209924.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32399139-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.*369A>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.*369A>G		3_prime_UTR_variant	27/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.*369A>G		3_prime_UTR_variant	27/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2684A>G		non_coding_transcript_exon_variant	26/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2684A>G		3_prime_UTR_variant	26/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40817 AN: 151510 Hom.: 5784 Cov.: 30

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.203 AC: 16204 AN: 79740 Hom.: 2181 Cov.: 0 AF XY: 0.200 AC XY: 7567 AN XY: 37906

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.0944

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.270 AC: 40865 AN: 151626 Hom.: 5789 Cov.: 30 AF XY: 0.266 AC XY: 19677 AN XY: 74054

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.0753

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.239

Alfa AF: 0.274 Hom.: 1177

Bravo AF: 0.267

Asia WGS AF: 0.155 AC: 536 AN: 3468

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 0.06294 (Asian), 0.3435 (African), 0.277 (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 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 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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary cancer-predisposing syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.8
DANN	Benign	0.90

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: rs7334543; hg19: chr13-32973276;