rs1799943

Variant names:

• chr13-32316435-G-A
• rs1799943
• NM_000059.4:c.-26G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32316435-G-A
• chr13-32316435-G-C
• chr13-32316435-G-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.-26G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,601,606 control chromosomes in the GnomAD database, including 55,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3886 hom., cov: 33)
  • Exomes 𝑓: 0.26 (51773 hom.)
• Consequence: BRCA2 NM_000059.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:26 O:1
• Conservation: PhyloP100: 0.546
• Publications: 93 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 (BayesDel_noAF=-0.78).
• BP6: Variant 13-32316435-G-A is Benign according to our data. Variant chr13-32316435-G-A is described in ClinVar as Benign. ClinVar VariationId is 125965.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 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.-26G>A		5_prime_UTR	Exon 2 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.-26G>A		5_prime_UTR	Exon 2 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.-26G>A		5_prime_UTR	Exon 2 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.-26G>A		5_prime_UTR	Exon 2 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.-26G>A		5_prime_UTR	Exon 2 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.-391G>A		5_prime_UTR	Exon 2 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32462 AN: 152032 Hom.: 3894 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.246 AC: 61394 AN: 250044 AF XY: 0.251

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.262 AC: 379895 AN: 1449454 Hom.: 51773 Cov.: 30 AF XY: 0.264 AC XY: 190683 AN XY: 721840

African (AFR) AF: 0.0975 AC: 3235 AN: 33196

American (AMR) AF: 0.193 AC: 8622 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 7191 AN: 26062

East Asian (EAS) AF: 0.423 AC: 16762 AN: 39610

South Asian (SAS) AF: 0.287 AC: 24628 AN: 85894

European-Finnish (FIN) AF: 0.199 AC: 10637 AN: 53382

Middle Eastern (MID) AF: 0.233 AC: 1342 AN: 5756

European-Non Finnish (NFE) AF: 0.265 AC: 291944 AN: 1100914

Other (OTH) AF: 0.259 AC: 15534 AN: 59972

GnomAD4 genome AF: 0.213 AC: 32439 AN: 152152 Hom.: 3886 Cov.: 33 AF XY: 0.212 AC XY: 15766 AN XY: 74374

African (AFR) AF: 0.106 AC: 4386 AN: 41520

American (AMR) AF: 0.189 AC: 2896 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3466

East Asian (EAS) AF: 0.387 AC: 1999 AN: 5168

South Asian (SAS) AF: 0.279 AC: 1345 AN: 4822

European-Finnish (FIN) AF: 0.191 AC: 2024 AN: 10584

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18105 AN: 67986

Other (OTH) AF: 0.225 AC: 477 AN: 2116

Alfa AF: 0.251 Hom.: 21826

Bravo AF: 0.207

Asia WGS AF: 0.255 AC: 889 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	Breast-ovarian cancer, familial, susceptibility to, 2 (10)
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Familial cancer of breast (2)
-	-	1	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.8
DANN	Benign	0.66
PhyloP100		0.55
PromoterAI		-0.0063	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1799943; hg19: chr13-32890572; COSMIC: COSV61525225; COSMIC: COSV61525225;