rs3764792

Variant names:

• chr13-32376978-C-T
• rs3764792
• NM_000059.4:c.8754+187C>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.8754+187C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 151,778 control chromosomes in the GnomAD database, including 3,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.22 (3676 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.346
• Publications: 7 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=-0.82).
• BP6: Variant 13-32376978-C-T is Benign according to our data. Variant chr13-32376978-C-T is described in ClinVar as Benign. ClinVar VariationId is 209837.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 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.8754+187C>T		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.8754+187C>T		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.8754+187C>T		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.8754+187C>T		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8754+187C>T		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8385+187C>T		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33000 AN: 151662 Hom.: 3676 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.217 AC: 33003 AN: 151778 Hom.: 3676 Cov.: 32 AF XY: 0.221 AC XY: 16398 AN XY: 74154

African (AFR) AF: 0.204 AC: 8431 AN: 41368

American (AMR) AF: 0.183 AC: 2791 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3466

East Asian (EAS) AF: 0.394 AC: 2026 AN: 5140

South Asian (SAS) AF: 0.221 AC: 1063 AN: 4810

European-Finnish (FIN) AF: 0.239 AC: 2506 AN: 10506

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14804 AN: 67924

Other (OTH) AF: 0.218 AC: 461 AN: 2112

Alfa AF: 0.221 Hom.: 500

Bravo AF: 0.214

Asia WGS AF: 0.254 AC: 885 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.64
PhyloP100		0.35
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: rs3764792; hg19: chr13-32951115; COSMIC: COSV101204400; COSMIC: COSV101204400;