rs1799944

Variant names:

• chr13-32337326-A-G
• rs1799944
• NM_000059.4:c.2971A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32337326-A-G
• chr13-32337326-A-C
• chr13-32337326-A-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.2971A>G​(p.Asn991Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,613,690 control chromosomes in the GnomAD database, including 2,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N991K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (247 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2003 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:37 O:2
• Conservation: PhyloP100: -0.0400
• Publications: 151 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002044946).
• BP6: Variant 13-32337326-A-G is Benign according to our data. Variant chr13-32337326-A-G is described in ClinVar as Benign. ClinVar VariationId is 41545.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.2971A>G	p.Asn991Asp	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.2971A>G	p.Asn991Asp	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.2971A>G	p.Asn991Asp	missense	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.2971A>G	p.Asn991Asp	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.2971A>G	p.Asn991Asp	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.2602A>G	p.Asn868Asp	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7127 AN: 152182 Hom.: 244 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0984

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0541 AC: 13545 AN: 250428 AF XY: 0.0568

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.0727

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.0351

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0428 AC: 62505 AN: 1461390 Hom.: 2003 Cov.: 33 AF XY: 0.0453 AC XY: 32963 AN XY: 726978

African (AFR) AF: 0.0417 AC: 1396 AN: 33458

American (AMR) AF: 0.0758 AC: 3387 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 1078 AN: 26124

East Asian (EAS) AF: 0.119 AC: 4715 AN: 39634

South Asian (SAS) AF: 0.115 AC: 9907 AN: 86162

European-Finnish (FIN) AF: 0.0152 AC: 808 AN: 53316

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5762

European-Non Finnish (NFE) AF: 0.0342 AC: 38046 AN: 1111860

Other (OTH) AF: 0.0471 AC: 2844 AN: 60384

GnomAD4 genome AF: 0.0469 AC: 7149 AN: 152300 Hom.: 247 Cov.: 32 AF XY: 0.0493 AC XY: 3669 AN XY: 74478

African (AFR) AF: 0.0425 AC: 1768 AN: 41572

American (AMR) AF: 0.0991 AC: 1516 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3466

East Asian (EAS) AF: 0.0997 AC: 516 AN: 5176

South Asian (SAS) AF: 0.114 AC: 550 AN: 4828

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0345 AC: 2346 AN: 68016

Other (OTH) AF: 0.0516 AC: 109 AN: 2114

Alfa AF: 0.0390 Hom.: 640

Bravo AF: 0.0489

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.0366 AC: 314

ExAC AF: 0.0531 AC: 6448

Asia WGS AF: 0.111 AC: 385 AN: 3476

EpiCase AF: 0.0363

EpiControl AF: 0.0391

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	Breast-ovarian cancer, familial, susceptibility to, 2 (12)
-	-	9	not specified (10)
-	-	6	not provided (6)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	2	Familial cancer of breast (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast carcinoma (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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.24
DANN	Benign	0.15
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0056	N
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.040
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.051
MPC		0.021
ClinPred		0.00095	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.063
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: rs1799944; hg19: chr13-32911463; COSMIC: COSV66450658; COSMIC: COSV66450658;