chr13-32379413-G-A

Variant names:

• chr13-32379413-G-A
• rs11571769
• NM_000059.4:c.8851G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.8851G>A​(p.Ala2951Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,613,810 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts 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. A2951G) has been classified as Uncertain significance. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0084 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (96 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:46 O:1
• Conservation: PhyloP100: 7.91
• Publications: 77 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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005076319).
• BP6: Variant 13-32379413-G-A is Benign according to our data. Variant chr13-32379413-G-A is described in ClinVar as Benign. ClinVar VariationId is 41570.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00841 (1281/152290) while in subpopulation AMR AF = 0.0508 (777/15300). AF 95% confidence interval is 0.0478. There are 38 homozygotes in GnomAd4. There are 724 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR,AD 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.8851G>A	p.Ala2951Thr	missense	Exon 22 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8851G>A	p.Ala2951Thr	missense	Exon 22 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8851G>A	p.Ala2951Thr	missense	Exon 22 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.8851G>A	p.Ala2951Thr	missense	Exon 22 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8851G>A	p.Ala2951Thr	missense	Exon 22 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8482G>A	p.Ala2828Thr	missense	Exon 22 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152172 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00955 AC: 2395 AN: 250796 AF XY: 0.00886

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00677 AC: 9893 AN: 1461520 Hom.: 96 Cov.: 31 AF XY: 0.00681 AC XY: 4951 AN XY: 727048

African (AFR) AF: 0.00114 AC: 38 AN: 33458

American (AMR) AF: 0.0392 AC: 1751 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26120

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39662

South Asian (SAS) AF: 0.0146 AC: 1256 AN: 86188

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53412

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.00574 AC: 6378 AN: 1111850

Other (OTH) AF: 0.00620 AC: 374 AN: 60368

GnomAD4 genome AF: 0.00841 AC: 1281 AN: 152290 Hom.: 38 Cov.: 33 AF XY: 0.00972 AC XY: 724 AN XY: 74480

African (AFR) AF: 0.00123 AC: 51 AN: 41554

American (AMR) AF: 0.0508 AC: 777 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68008

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00536 Hom.: 18

Bravo AF: 0.00992

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00563

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	13	Breast-ovarian cancer, familial, susceptibility to, 2 (13)
-	-	10	not specified (11)
-	-	6	not provided (6)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	2	Familial cancer of breast (2)
-	-	2	Malignant tumor of breast (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia complementation group D1 (1)
1	-	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0051	T
MetaSVM	Uncertain	-0.23	T
PhyloP100		7.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.51
MVP		0.89
MPC		0.16
ClinPred		0.020	T
GERP RS		5.6
gMVP		0.33
Mutation Taster		=94/6	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: rs11571769; hg19: chr13-32953550; COSMIC: COSV66463542; COSMIC: COSV66463542;