13-32394673-T-C

Position:

• chr13-32394673-T-C

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.9257-16T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,609,366 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: BRCA2 NM_000059.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:25
• Conservation: PhyloP100: 0.00

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=-0.84).
• BP6: Variant 13-32394673-T-C is Benign according to our data. Variant chr13-32394673-T-C is described in ClinVar as [Benign]. Clinvar id is 52790.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394673-T-C is described in Lovd as [Benign]. Variant chr13-32394673-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00601 (915/152358) while in subpopulation NFE AF= 0.0085 (578/68034). AF 95% confidence interval is 0.00792. There are 3 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9257-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9257-16T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 916 AN: 152240 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00849

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00659 AC: 1610 AN: 244488 Hom.: 15 AF XY: 0.00687 AC XY: 910 AN XY: 132364

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00692

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00807 AC: 11761 AN: 1457008 Hom.: 69 Cov.: 31 AF XY: 0.00823 AC XY: 5961 AN XY: 724638

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.00449

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00896

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152358 Hom.: 3 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74506

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00850

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00596 Hom.: 0

Bravo AF: 0.00539

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:9

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 22, 2016	- -
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 0.01055 (European), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 15, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Apr 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 c.9257-16T>C variant was identified in 121 of 53524 proband chromosomes (frequency: 0.002) from individuals or families with Breast and Ovarian cancer, and was present in 4 of 530 control chromosomes (frequency: 0.08) from healthy individuals (Caputo 2011, Borg 2010, Hadijisavvas 2003, Cvok 2008, Diez 2003). The variant was identified in dbSNP (ID: rs11571818) with “other” allele, with a minor allele frequency of 0.0044(1000 Genomes Project); in NHLBI Exome Sequencing Project (Exome Variant Server) in 67 of 8600 European and 10 of 4406 African Americans; in Exome Aggregation Consortium (ExAC) database in 574(3 homozygote) of 56204 of Europeans(non-Finnish), in 15 of 9522 Africans, in 25 of 10298 Latinos, in 116 (4 homozygote) of 15288 South Asians , in 77 (2 homozygote) of 6222 Europeans (Finnish) and 5 of 820 other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, classified as benign by Invitae, as benign by Counsyl, as benign by GeneDX, as benign by Emory Genetics, as Likely benign by CHEO and as uncertain significance by BIC). It was also identified in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “likely benign” by a clinical laboratory), the BIC database (12X with no clinical importance), and UMD (73X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.5116G>A (p.Gly1706Arg), c.4391delC (p.Pro1464LeufsX2), c.81_134delp.Cys27X); BRCA2:c.6275_6276delTT (p.Leu2092ProfsX7), c.4889C>G (p.Ser1630X), increasing the likelihood that the c.9257-16T>C variant does not have clinical significance. The c.9257-16T>C 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 splicing studies (Bonnet 2008, Claes 2003) showed that the c.9257-16T>C do not result in aberrant splicing. 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 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. -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 28, 2021

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.32

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: rs11571818; hg19: chr13-32968810; COSMIC: COSV104701316; COSMIC: COSV104701316;