13-32395894-T-C

Variant names:

• chr13-32395894-T-C
• rs1012130
• NM_000059.4:c.9501+961T>C

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.9501+961T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 189,324 control chromosomes in the GnomAD database, including 6,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4991 hom., cov: 29)
  • Exomes 𝑓: 0.21 (1245 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.191
• Publications: 10 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=-0.86).
• BP6: Variant 13-32395894-T-C is Benign according to our data. Variant chr13-32395894-T-C is described in ClinVar as Benign. ClinVar VariationId is 209912.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9501+961T>C		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.9501+961T>C		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.9450+961T>C		intron	N/A	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9501+961T>C		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9501+961T>C		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.9132+961T>C		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37649 AN: 150730 Hom.: 4987 Cov.: 29

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.208 AC: 7992 AN: 38482 Hom.: 1245 AF XY: 0.199 AC XY: 4817 AN XY: 24184

African (AFR) AF: 0.179 AC: 61 AN: 340

American (AMR) AF: 0.294 AC: 481 AN: 1638

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 101 AN: 520

East Asian (EAS) AF: 0.0547 AC: 42 AN: 768

South Asian (SAS) AF: 0.111 AC: 1020 AN: 9166

European-Finnish (FIN) AF: 0.289 AC: 487 AN: 1684

Middle Eastern (MID) AF: 0.132 AC: 15 AN: 114

European-Non Finnish (NFE) AF: 0.241 AC: 5475 AN: 22714

Other (OTH) AF: 0.202 AC: 310 AN: 1538

GnomAD4 genome AF: 0.250 AC: 37692 AN: 150842 Hom.: 4991 Cov.: 29 AF XY: 0.248 AC XY: 18228 AN XY: 73614

African (AFR) AF: 0.234 AC: 9608 AN: 41070

American (AMR) AF: 0.274 AC: 4146 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 750 AN: 3464

East Asian (EAS) AF: 0.0816 AC: 422 AN: 5174

South Asian (SAS) AF: 0.134 AC: 645 AN: 4796

European-Finnish (FIN) AF: 0.320 AC: 3227 AN: 10092

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.267 AC: 18118 AN: 67806

Other (OTH) AF: 0.231 AC: 486 AN: 2102

Alfa AF: 0.249 Hom.: 5586

Bravo AF: 0.250

Asia WGS AF: 0.155 AC: 536 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.0
DANN	Benign	0.81
PhyloP100		0.19
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: rs1012130; hg19: chr13-32970031;