13-32362509-T-C

Variant names:

• chr13-32362509-T-C
• rs9534262
• NM_000059.4:c.7806-14T>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.7806-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,608,568 control chromosomes in the GnomAD database, including 223,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22039 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201271 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: -1.41
• Publications: 70 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):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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=-0.74).
• BP6: Variant 13-32362509-T-C is Benign according to our data. Variant chr13-32362509-T-C is described in ClinVar as Benign. ClinVar VariationId is 126158.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.561 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7806-14T>C		intron	N/A	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7806-14T>C		intron	N/A	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7806-14T>C		intron	N/A	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7806-14T>C		intron	N/A	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7806-14T>C		intron	N/A	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7437-14T>C		intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81547 AN: 151850 Hom.: 22016 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.518

GnomAD2 exomes AF: 0.523 AC: 130837 AN: 250228 AF XY: 0.520

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.524 AC: 763705 AN: 1456600 Hom.: 201271 Cov.: 35 AF XY: 0.523 AC XY: 379264 AN XY: 724988

African (AFR) AF: 0.557 AC: 18552 AN: 33312

American (AMR) AF: 0.514 AC: 22952 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12436 AN: 26110

East Asian (EAS) AF: 0.608 AC: 24117 AN: 39648

South Asian (SAS) AF: 0.489 AC: 42139 AN: 86110

European-Finnish (FIN) AF: 0.574 AC: 30677 AN: 53398

Middle Eastern (MID) AF: 0.409 AC: 2349 AN: 5744

European-Non Finnish (NFE) AF: 0.523 AC: 579167 AN: 1107380

Other (OTH) AF: 0.520 AC: 31316 AN: 60206

GnomAD4 genome AF: 0.537 AC: 81625 AN: 151968 Hom.: 22039 Cov.: 32 AF XY: 0.540 AC XY: 40088 AN XY: 74292

African (AFR) AF: 0.567 AC: 23480 AN: 41422

American (AMR) AF: 0.536 AC: 8191 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1645 AN: 3472

East Asian (EAS) AF: 0.571 AC: 2960 AN: 5182

South Asian (SAS) AF: 0.480 AC: 2314 AN: 4822

European-Finnish (FIN) AF: 0.572 AC: 6025 AN: 10540

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35407 AN: 67948

Other (OTH) AF: 0.516 AC: 1088 AN: 2108

Alfa AF: 0.518 Hom.: 44682

Bravo AF: 0.533

Asia WGS AF: 0.526 AC: 1830 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	Breast-ovarian cancer, familial, susceptibility to, 2 (10)
-	-	9	not specified (9)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Familial cancer of breast (2)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.5
DANN	Benign	0.81
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9534262; hg19: chr13-32936646; COSMIC: COSV66447577;