chr13-32326296-C-T

Position:

• chr13-32326296-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.516+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,609,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.225

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-32326296-C-T is Benign according to our data. Variant chr13-32326296-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 132764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32326296-C-T is described in Lovd as [Benign]. Variant chr13-32326296-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.516+14C>T		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.516+14C>T		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000359 AC: 90 AN: 250544 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1456916 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 725138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000560

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74408

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000442

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2020	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 c.516+14C>T variant has been shown not to impact mRNA splicing in in vitro splicing assays (Bonnet 2008, Houdayer2012). The variant was identified in dbSNP (ID: rs rs182828913) “With benign allele”, with a minor allele frequency of .0006/3 (1000 Genomes Project, in 3 of 5000 chromosomes, frequency 0.0006), the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 36 of 116930 chromosomes (frequency: 0.0003) (or 5 individuals from a population of 63686 European (Non-Finnish) individuals, 31 of 11264 Latino individuals, and none from East Asian, Other, African, South Asian or European (Finnish) individuals; Clinvitae database (2X as benign/likely benign), the ClinVar database (classified as a benign variant by Invitae and GeneDX), GeneInsight COGR database (1X, unclassified by a clinical laboratory), and UMD (12X as a likely neutral variant, with a co-occurring pathogenic BRCA1 variant (c.-200_80del (p.Met1SerfsX13)), increasing the likelihood that the c.516+14C>T variant does not have clinical significance. The variant was also identified by our laboratory in 1 individual with breast cancer. 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 summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	Variant summary: The BRCA2 c.516+14C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing, which was confirmed by multiple functional studies (Bonnet_2008, Houdayer_2012, Menendez_2012, de Garibay_2014). Although this variant has been reported in breast cancer patients, this variant was also found in 36/117190 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0027521 (31/11264). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, co-occurrences of this variant and a pathogenic BRCA1 variant have been reported in at least two patients (Garcia-Casado_2011 and UMD database). Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 09, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 25, 2015

- -

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	-0.73
CADD	Benign	8.8
DANN	Benign	0.67

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: rs182828913; hg19: chr13-32900433;