rs10492396

chr13-32384750-G-A

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.9256+4605G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 254,848 control chromosomes in the GnomAD database, including 500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.048 (265 hom., cov: 32)
  • Exomes 𝑓: 0.058 (235 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.48

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]

IFIT1P1 (HGNC:5408): (interferon induced protein with tetratricopeptide repeats 1 pseudogene 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 13-32384750-G-A is Benign according to our data. Variant chr13-32384750-G-A is described in ClinVar as [Benign]. Clinvar id is 209866.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32384750-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9256+4605G>A		intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9256+4605G>A		intron_variant		5	NM_000059.4	A2
IFIT1P1	ENST00000400497.2	n.91G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 7277 AN: 152196 Hom.: 265 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0497

GnomAD4 exome AF: 0.0577 AC: 5921 AN: 102534 Hom.: 235 Cov.: 0 AF XY: 0.0586 AC XY: 3391 AN XY: 57846

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.0696

Gnomad4 EAS exome AF: 0.000174

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0945

Gnomad4 NFE exome AF: 0.0654

Gnomad4 OTH exome AF: 0.0567

GnomAD4 genome AF: 0.0478 AC: 7278 AN: 152314 Hom.: 265 Cov.: 32 AF XY: 0.0487 AC XY: 3625 AN XY: 74494

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0400

Gnomad4 ASJ AF: 0.0838

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.0654

Gnomad4 OTH AF: 0.0491

Alfa AF: 0.0619 Hom.: 66

Bravo AF: 0.0422

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

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 0.06728 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	8.5
Dann	Benign	0.79

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: rs10492396; hg19: chr13-32958887;