rs36060526

Variant names:

• chr13-32337619-T-C
• rs36060526
• NM_000059.4:c.3264T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32337619-T-C
• chr13-32337619-T-A

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.3264T>C​(p.Pro1088Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,589,920 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (8 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:33
• Conservation: PhyloP100: 0.300
• Publications: 8 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=-0.89).
• BP6: Variant 13-32337619-T-C is Benign according to our data. Variant chr13-32337619-T-C is described in ClinVar as Benign. ClinVar VariationId is 51435.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0072 (1097/152270) while in subpopulation AFR AF = 0.025 (1041/41570). AF 95% confidence interval is 0.0238. There are 16 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.3264T>C	p.Pro1088Pro	synonymous	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.3264T>C	p.Pro1088Pro	synonymous	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.3264T>C	p.Pro1088Pro	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.3264T>C	p.Pro1088Pro	synonymous	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.3264T>C	p.Pro1088Pro	synonymous	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.2895T>C	p.Pro965Pro	synonymous	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152152 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00190 AC: 442 AN: 232046 AF XY: 0.00140

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000697 AC: 1002 AN: 1437650 Hom.: 8 Cov.: 33 AF XY: 0.000619 AC XY: 441 AN XY: 713004

African (AFR) AF: 0.0248 AC: 797 AN: 32136

American (AMR) AF: 0.00125 AC: 50 AN: 40158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24932

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39474

South Asian (SAS) AF: 0.000122 AC: 10 AN: 81818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52660

Middle Eastern (MID) AF: 0.000711 AC: 4 AN: 5626

European-Non Finnish (NFE) AF: 0.0000418 AC: 46 AN: 1101640

Other (OTH) AF: 0.00159 AC: 94 AN: 59206

GnomAD4 genome AF: 0.00720 AC: 1097 AN: 152270 Hom.: 16 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74460

African (AFR) AF: 0.0250 AC: 1041 AN: 41570

American (AMR) AF: 0.00249 AC: 38 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00807

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	7	Breast-ovarian cancer, familial, susceptibility to, 2 (8)
-	-	6	not specified (6)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Familial cancer of breast (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Malignant tumor of breast (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	-0.89
CADD	Benign	2.4
DANN	Benign	0.45
PhyloP100		0.30
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: rs36060526; hg19: chr13-32911756; COSMIC: COSV104430714;