rs10492396

Variant names:

• chr13-32384750-G-A
• rs10492396
• NM_000059.4:c.9256+4605G>A

Variant summary

Our verdict is Benign. The variant received -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:2
• Conservation: PhyloP100: 1.48
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 209866.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9256+4605G>A		intron_variant	Intron 24 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9256+4605G>A		intron_variant	Intron 24 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8887+4605G>A		intron_variant	Intron 24 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1314+4605G>A		intron_variant	Intron 23 of 25	2		ENSP00000506251.1

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

African (AFR) AF: 0.0170 AC: 44 AN: 2594

American (AMR) AF: 0.0300 AC: 291 AN: 9706

Ashkenazi Jewish (ASJ) AF: 0.0696 AC: 133 AN: 1912

East Asian (EAS) AF: 0.000174 AC: 1 AN: 5750

South Asian (SAS) AF: 0.0173 AC: 145 AN: 8394

European-Finnish (FIN) AF: 0.0945 AC: 1708 AN: 18072

Middle Eastern (MID) AF: 0.0473 AC: 87 AN: 1840

European-Non Finnish (NFE) AF: 0.0654 AC: 3262 AN: 49856

Other (OTH) AF: 0.0567 AC: 250 AN: 4410

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

African (AFR) AF: 0.0112 AC: 464 AN: 41580

American (AMR) AF: 0.0400 AC: 612 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 291 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4826

European-Finnish (FIN) AF: 0.105 AC: 1116 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0654 AC: 4445 AN: 68008

Other (OTH) AF: 0.0491 AC: 104 AN: 2116

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:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.06728 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10492396; hg19: chr13-32958887;