rs28897743

Variant names:

• chr13-32346896-G-A
• rs28897743
• NM_000059.4:c.7007G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32346896-G-A
• chr13-32346896-G-C
• chr13-32346896-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7007G>A​(p.Arg2336His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000062 in 1,450,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic reviewed by expert panel P:40
• Conservation: PhyloP100: 4.66
• Publications: 113 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: Pathogenic. The variant received 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 13-32346896-G-A is Pathogenic according to our data. Variant chr13-32346896-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.

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.7007G>A	p.Arg2336His	missense splice_region	Exon 13 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7007G>A	p.Arg2336His	missense splice_region	Exon 13 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7007G>A	p.Arg2336His	missense splice_region	Exon 13 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7007G>A	p.Arg2336His	missense splice_region	Exon 13 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7007G>A	p.Arg2336His	missense splice_region	Exon 13 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6638G>A	p.Arg2213His	missense splice_region	Exon 13 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247222 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1450870 Hom.: 0 Cov.: 29 AF XY: 0.00000970 AC XY: 7 AN XY: 721902

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000724 AC: 8 AN: 1105500

Other (OTH) AF: 0.00 AC: 0 AN: 59960

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000486 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (13)
9	-	-	not provided (9)
5	-	-	Hereditary cancer-predisposing syndrome (5)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
3	-	-	Fanconi anemia complementation group D1 (3)
2	-	-	Breast and/or ovarian cancer (2)
1	-	-	BRCA2-related disorder (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Inherited breast cancer and ovarian cancer (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
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.61	T
PhyloP100		4.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.046	D
Vest4		0.44
MutPred		0.69		Loss of glycosylation at T2331 (P = 0.1361)
MVP		0.90
MPC		0.067
ClinPred		0.95	D
GERP RS		5.0
gMVP		0.20
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
Splicevardb		3.0
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28897743; hg19: chr13-32921033; COSMIC: COSV66456373;