13-32337158-G-A

Variant names:

• chr13-32337158-G-A
• rs28897716
• NM_000059.4:c.2803G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000059.4(BRCA2):​c.2803G>A​(p.Asp935Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,826 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D935E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:33 O:1
• Conservation: PhyloP100: 0.312
• Publications: 51 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11293295).
• BP6: Variant 13-32337158-G-A is Benign according to our data. Variant chr13-32337158-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 51349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2803G>A	p.Asp935Asn	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.2803G>A	p.Asp935Asn	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.2803G>A	p.Asp935Asn	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.2803G>A	p.Asp935Asn	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.2803G>A	p.Asp935Asn	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.2434G>A	p.Asp812Asn	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.000985

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000606 AC: 152 AN: 250844 AF XY: 0.000590

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00121 AC: 1767 AN: 1461536 Hom.: 4 Cov.: 33 AF XY: 0.00115 AC XY: 839 AN XY: 727068

African (AFR) AF: 0.000209 AC: 7 AN: 33466

American (AMR) AF: 0.000582 AC: 26 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53398

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00150 AC: 1672 AN: 1111858

Other (OTH) AF: 0.000928 AC: 56 AN: 60374

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74468

African (AFR) AF: 0.000313 AC: 13 AN: 41570

American (AMR) AF: 0.00105 AC: 16 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68000

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000963 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
-	-	8	not specified (9)
-	-	5	not provided (5)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.060	N
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.092
Sift	Benign	0.043	D
Sift4G	Benign	0.090	T
Vest4		0.44
MVP		0.85
MPC		0.027
ClinPred		0.015	T
GERP RS		-0.46
gMVP		0.16
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28897716; hg19: chr13-32911295; COSMIC: COSV104701327;