chr13-32385103-C-A

Variant names:

• chr13-32385103-C-A
• rs11571789
• NM_000059.4:c.9256+4958C>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+4958C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 256,520 control chromosomes in the GnomAD database, including 1,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.080 (707 hom., cov: 32)
  • Exomes 𝑓: 0.094 (538 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 2.72
• Publications: 8 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=-0.61).
• BP6: Variant 13-32385103-C-A is Benign according to our data. Variant chr13-32385103-C-A is described in ClinVar as Benign. ClinVar VariationId is 209869.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9256+4958C>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+4958C>A		intron_variant	Intron 24 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8887+4958C>A		intron_variant	Intron 24 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1314+4958C>A		intron_variant	Intron 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12153 AN: 152056 Hom.: 707 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0811

GnomAD4 exome AF: 0.0935 AC: 9760 AN: 104346 Hom.: 538 Cov.: 0 AF XY: 0.0938 AC XY: 5242 AN XY: 55856

African (AFR) AF: 0.0160 AC: 50 AN: 3124

American (AMR) AF: 0.0293 AC: 212 AN: 7234

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 304 AN: 2578

East Asian (EAS) AF: 0.000965 AC: 7 AN: 7252

South Asian (SAS) AF: 0.0473 AC: 250 AN: 5290

European-Finnish (FIN) AF: 0.165 AC: 2909 AN: 17622

Middle Eastern (MID) AF: 0.0589 AC: 95 AN: 1614

European-Non Finnish (NFE) AF: 0.100 AC: 5418 AN: 54188

Other (OTH) AF: 0.0946 AC: 515 AN: 5444

GnomAD4 genome AF: 0.0798 AC: 12151 AN: 152174 Hom.: 707 Cov.: 32 AF XY: 0.0841 AC XY: 6255 AN XY: 74394

African (AFR) AF: 0.0185 AC: 768 AN: 41556

American (AMR) AF: 0.0564 AC: 863 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5174

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4822

European-Finnish (FIN) AF: 0.184 AC: 1948 AN: 10562

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7579 AN: 67992

Other (OTH) AF: 0.0802 AC: 169 AN: 2106

Alfa AF: 0.0925 Hom.: 981

Bravo AF: 0.0665

Asia WGS AF: 0.0290 AC: 103 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 0.1253 (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	-0.61
CADD	Benign	9.5
DANN	Benign	0.74
PhyloP100		2.7
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: rs11571789; hg19: chr13-32959240;