13-32370604-C-T

Position:

chr13-32370604-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: -0.397

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.8487+47C>T		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.8487+47C>T		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2082

AN:

152072

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00259

AC XY:

336

AN XY:

129888

show subpopulations

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.:

Cov.:

AF XY:

0.00128

AC XY:

905

AN XY:

709134

show subpopulations

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.:

Cov.:

AF XY:

0.0130

AC XY:

966

AN XY:

74404

show subpopulations

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.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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). -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

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