13-32339554-C-T

Variant names:

• chr13-32339554-C-T
• rs28897734
• NM_000059.4:c.5199C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000059.4(BRCA2):​c.5199C>T​(p.Ser1733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,607,272 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S1733S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (42 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:36
• Conservation: PhyloP100: -0.989
• Publications: 28 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-32339554-C-T is Benign according to our data. Variant chr13-32339554-C-T is described in ClinVar as Benign. ClinVar VariationId is 51813.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.989 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00467 (711/152094) while in subpopulation NFE AF = 0.00693 (471/67970). AF 95% confidence interval is 0.00641. There are 8 homozygotes in GnomAd4. There are 339 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.5199C>T	p.Ser1733Ser	synonymous	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.5199C>T	p.Ser1733Ser	synonymous	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.5199C>T	p.Ser1733Ser	synonymous	Exon 11 of 27	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.5199C>T	p.Ser1733Ser	synonymous	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.5199C>T	p.Ser1733Ser	synonymous	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.4830C>T	p.Ser1610Ser	synonymous	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 711 AN: 151976 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00693

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00451 AC: 1111 AN: 246572 AF XY: 0.00435

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.000548

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00568

GnomAD4 exome AF: 0.00503 AC: 7323 AN: 1455178 Hom.: 42 Cov.: 45 AF XY: 0.00507 AC XY: 3668 AN XY: 723876

African (AFR) AF: 0.000543 AC: 18 AN: 33160

American (AMR) AF: 0.00291 AC: 128 AN: 43988

Ashkenazi Jewish (ASJ) AF: 0.00698 AC: 181 AN: 25926

East Asian (EAS) AF: 0.000632 AC: 25 AN: 39580

South Asian (SAS) AF: 0.000565 AC: 48 AN: 84954

European-Finnish (FIN) AF: 0.0110 AC: 586 AN: 53290

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5722

European-Non Finnish (NFE) AF: 0.00550 AC: 6100 AN: 1108462

Other (OTH) AF: 0.00386 AC: 232 AN: 60096

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152094 Hom.: 8 Cov.: 33 AF XY: 0.00456 AC XY: 339 AN XY: 74346

African (AFR) AF: 0.000916 AC: 38 AN: 41506

American (AMR) AF: 0.00374 AC: 57 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00693 AC: 471 AN: 67970

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00546 Hom.: 4

Bravo AF: 0.00369

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	9	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.20
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism

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: rs28897734; hg19: chr13-32913691; COSMIC: COSV66455665;