rs3752451

Variant names:

• chr13-32326796-T-A
• rs3752451
• NM_000059.4:c.631+183T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32326796-T-A
• chr13-32326796-T-G

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.631+183T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,724 control chromosomes in the GnomAD database, including 8,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.33 (8620 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.0330
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.93).
• BP6: Variant 13-32326796-T-A is Benign according to our data. Variant chr13-32326796-T-A is described in ClinVar as Benign. ClinVar VariationId is 209652.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 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.631+183T>A		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.631+183T>A		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.631+183T>A		intron	N/A	NP_001393649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.631+183T>A		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.631+183T>A		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.262+183T>A		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50638 AN: 151606 Hom.: 8620 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.334 AC: 50653 AN: 151724 Hom.: 8620 Cov.: 32 AF XY: 0.338 AC XY: 25036 AN XY: 74172

African (AFR) AF: 0.284 AC: 11730 AN: 41316

American (AMR) AF: 0.326 AC: 4968 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1216 AN: 3466

East Asian (EAS) AF: 0.499 AC: 2576 AN: 5164

South Asian (SAS) AF: 0.409 AC: 1957 AN: 4790

European-Finnish (FIN) AF: 0.332 AC: 3508 AN: 10558

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.350 AC: 23722 AN: 67858

Other (OTH) AF: 0.328 AC: 693 AN: 2110

Alfa AF: 0.344 Hom.: 1140

Bravo AF: 0.325

Asia WGS AF: 0.392 AC: 1364 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		0.033
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: rs3752451; hg19: chr13-32900933;