13-32355341-C-T

Position:

• chr13-32355341-C-T

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.7435+53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,587,692 control chromosomes in the GnomAD database, including 2,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.041 (220 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1922 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: -0.300

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=-0.91).
• BP6: Variant 13-32355341-C-T is Benign according to our data. Variant chr13-32355341-C-T is described in ClinVar as [Benign]. Clinvar id is 126136.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32355341-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7435+53C>T		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7435+53C>T		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6164 AN: 152018 Hom.: 217 Cov.: 31

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0974

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0474

GnomAD4 exome AF: 0.0417 AC: 59897 AN: 1435556 Hom.: 1922 Cov.: 31 AF XY: 0.0444 AC XY: 31734 AN XY: 714762

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.0752

Gnomad4 ASJ exome AF: 0.0401

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0337

Gnomad4 OTH exome AF: 0.0452

GnomAD4 genome AF: 0.0406 AC: 6183 AN: 152136 Hom.: 220 Cov.: 31 AF XY: 0.0433 AC XY: 3223 AN XY: 74396

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.0981

Gnomad4 ASJ AF: 0.0430

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0340

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0308 Hom.: 10

Bravo AF: 0.0419

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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	GeneKor MSA	Nov 01, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
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 0.1031 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	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. -

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	-0.91
CADD	Benign	3.5
DANN	Benign	0.54

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: rs11147489; hg19: chr13-32929478;