rs542551

Variant names:

• chr13-32385397-A-G
• rs542551
• NM_000059.4:c.9256+5252A>G

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+5252A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 216,724 control chromosomes in the GnomAD database, including 6,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4266 hom., cov: 32)
  • Exomes 𝑓: 0.26 (2160 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 2.10
• Publications: 9 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=-0.88).
• BP6: Variant 13-32385397-A-G is Benign according to our data. Variant chr13-32385397-A-G is described in ClinVar as Benign. ClinVar VariationId is 209870.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9256+5252A>G		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+5252A>G		intron_variant	Intron 24 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8887+5252A>G		intron_variant	Intron 24 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1314+5252A>G		intron_variant	Intron 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33979 AN: 151994 Hom.: 4264 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.258 AC: 16649 AN: 64614 Hom.: 2160 Cov.: 0 AF XY: 0.260 AC XY: 9870 AN XY: 37904

African (AFR) AF: 0.126 AC: 233 AN: 1850

American (AMR) AF: 0.305 AC: 2546 AN: 8354

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 330 AN: 910

East Asian (EAS) AF: 0.192 AC: 739 AN: 3856

South Asian (SAS) AF: 0.305 AC: 2204 AN: 7216

European-Finnish (FIN) AF: 0.212 AC: 1698 AN: 8028

Middle Eastern (MID) AF: 0.261 AC: 36 AN: 138

European-Non Finnish (NFE) AF: 0.260 AC: 8276 AN: 31886

Other (OTH) AF: 0.247 AC: 587 AN: 2376

GnomAD4 genome AF: 0.223 AC: 33994 AN: 152110 Hom.: 4266 Cov.: 32 AF XY: 0.222 AC XY: 16535 AN XY: 74366

African (AFR) AF: 0.122 AC: 5059 AN: 41512

American (AMR) AF: 0.283 AC: 4324 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3468

East Asian (EAS) AF: 0.183 AC: 944 AN: 5164

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4820

European-Finnish (FIN) AF: 0.204 AC: 2156 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17906 AN: 67960

Other (OTH) AF: 0.254 AC: 536 AN: 2114

Alfa AF: 0.246 Hom.: 664

Bravo AF: 0.225

Asia WGS AF: 0.257 AC: 893 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 0.1923 (Asian), 0.09959 (African), 0.248 (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	-0.88
CADD	Benign	0.45
DANN	Benign	0.49
PhyloP100		2.1
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: rs542551; hg19: chr13-32959534; COSMIC: COSV66454454;