rs2320236

Positions:

• chr13-32336191-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.1910-74T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,485,862 control chromosomes in the GnomAD database, including 27,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3028 hom., cov: 32)
  • Exomes 𝑓: 0.19 (24586 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 1.70

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 13-32336191-T-C is Benign according to our data. Variant chr13-32336191-T-C is described in ClinVar as [Benign]. Clinvar id is 209687.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336191-T-C is described in Lovd as [Likely_benign]. Variant chr13-32336191-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1910-74T>C		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1910-74T>C		intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29544 AN: 152058 Hom.: 3023 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.188 AC: 251058 AN: 1333686 Hom.: 24586 AF XY: 0.186 AC XY: 122838 AN XY: 660080

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0579

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.194 AC: 29582 AN: 152176 Hom.: 3028 Cov.: 32 AF XY: 0.194 AC XY: 14451 AN XY: 74396

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.0831

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.184

Alfa AF: 0.187 Hom.: 3290

Bravo AF: 0.194

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

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

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

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 0.07343 (Asian), 0.2703 (African), 0.2018 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.80

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: rs2320236; hg19: chr13-32910328;