13-32370604-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):c.8487+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,574,010 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.014 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: -0.397

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=-0.87).
• BP6: Variant 13-32370604-C-T is Benign according to our data. Variant chr13-32370604-C-T is described in ClinVar as [Benign]. Clinvar id is 126179.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370604-C-T is described in Lovd as [Benign]. Variant chr13-32370604-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2083/152190) while in subpopulation AFR AF= 0.0475 (1971/41502). AF 95% confidence interval is 0.0457. There are 38 homozygotes in gnomad4. There are 966 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8487+47C>T		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8487+47C>T		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2082 AN: 152072 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00355 AC: 852 AN: 240012 Hom.: 17 AF XY: 0.00259 AC XY: 336 AN XY: 129888

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00147 AC: 2094 AN: 1421820 Hom.: 44 Cov.: 26 AF XY: 0.00128 AC XY: 905 AN XY: 709134

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000942

Gnomad4 FIN exome AF: 0.0000943

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00334

GnomAD4 genome AF: 0.0137 AC: 2083 AN: 152190 Hom.: 38 Cov.: 32 AF XY: 0.0130 AC XY: 966 AN XY: 74404

Gnomad4 AFR AF: 0.0475

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.000401 Hom.: 1

Bravo AF: 0.0152

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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 0.05488 (African), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Nov 30, 1998	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 c.8487+47C>T variant was identified in the literature. The variant was also identified in dbSNP (ID: rs11571744) “With Uncertain significance allele”, with a minor allele frequency of 0.0162 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database (X1), LOVD, the ClinVar database, GeneInsight COGR database (1X), the BIC database (2X with no clinical importance), and UMD (37X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 (c.1813dup (p.Ile605AsnfsX11); c.5576_5579delTTAA (p.Ile1859LysfsX3); c.1310_1313delAAGA (p.Lys437IlefsX22); BRCA2 (c.IVS16+6T>C (c.4986+6T>C); c.1488delT (p.Leu498SerfsX5)), increasing the likelihood that the c.8487+47C>T variant does not have clinical significance. In BIC database variant was reported to occur in outbred control reference groups at an allele frequency >1% (MAF>0.01), and classifies the variant as not pathogenic/low clinical significance. This variant was identified in the 1000 Genomes Project in 81 of 5000 chromosomes (frequency: 0.0162), Exome Variant Server project in 1 of 8600 European American and in 197 of 4404 African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 436 of 9658 chromosomes (frequency: 0.045) and nine times in homozygous state from a population of African individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in 39 of 91040 European (Non-Finnish)/ Latino / South Asian/European (Finnish) individuals, increasing the likelihood this could be a low frequency benign variant. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, global sequence diversity analysis identified the variant has global heterozygosity 0.018 and classified the variant as polymorphism (Wagner 1999). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

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

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.25
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: rs11571744; hg19: chr13-32944741; COSMIC: COSV66449045; COSMIC: COSV66449045;