13-32315889-C-T

Variant names:

• chr13-32315889-C-T
• rs9562605
• NM_000059.4:c.-40+222C>T

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.-40+222C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,230 control chromosomes in the GnomAD database, including 3,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.22 (3705 hom., cov: 33)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.895
• Publications: 14 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]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-32315889-C-T is Benign according to our data. Variant chr13-32315889-C-T is described in ClinVar as Benign. ClinVar VariationId is 209601.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.-40+222C>T		intron_variant	Intron 1 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.-40+222C>T		intron_variant	Intron 1 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.-405+222C>T		intron_variant	Intron 1 of 26	1		ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33324 AN: 152112 Hom.: 3709 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.219

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.219 AC: 33317 AN: 152230 Hom.: 3705 Cov.: 33 AF XY: 0.218 AC XY: 16245 AN XY: 74440

African (AFR) AF: 0.203 AC: 8453 AN: 41544

American (AMR) AF: 0.226 AC: 3459 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1699 AN: 5164

South Asian (SAS) AF: 0.261 AC: 1260 AN: 4828

European-Finnish (FIN) AF: 0.174 AC: 1844 AN: 10602

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15159 AN: 68004

Other (OTH) AF: 0.217 AC: 458 AN: 2114

Alfa AF: 0.217 Hom.: 6092

Bravo AF: 0.224

Asia WGS AF: 0.241 AC: 837 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 0.3199 (Asian), 0.1382 (African), 0.1939 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.1
DANN	Benign	0.91
PhyloP100		-0.90
PromoterAI		-0.12	Neutral
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: rs9562605; hg19: chr13-32890026;