rs80359076

Variant names:

• chr13-32370421-G-A
• rs80359076
• NM_000059.4:c.8351G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32370421-G-A
• chr13-32370421-G-T
• chr13-32370421-G-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PM5 PP3 PP5

The NM_000059.4(BRCA2):​c.8351G>A​(p.Arg2784Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001478300: The variant has a probability of pathogenicity of 1.0 (PS3_strong). Guidugli et al Cancer Res 2013" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2784L) has been classified as Likely pathogenic. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:13 B:1
• Conservation: PhyloP100: 9.94
• Publications: 35 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001478300: The variant has a probability of pathogenicity of 1.0 (PS3_strong). Guidugli et al Cancer Res 2013;73:265-275,Couch Lab); SCV005374633: Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:29988080, 29884841, 32444794); SCV000184238: This variant was shown to be deleterious in several functional assays including assessment of homology-directed repair activity (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102;233-248, Hart SN. Genet Med . 2019 01;21(1):71-80) and sensitivity to cisplatin (Mesman RLS. Genet Med . 2019 02;21(2):293-302) and PARP inhibitors (Ikegami M et al. Nat Commun, 2020 05;11:2573).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 23 uncertain in NM_000059.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32370421-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 491350.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• PP5: Variant 13-32370421-G-A is Pathogenic according to our data. Variant chr13-32370421-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52559.

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.8351G>A	p.Arg2784Gln	missense	Exon 19 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8351G>A	p.Arg2784Gln	missense	Exon 19 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8351G>A	p.Arg2784Gln	missense	Exon 19 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.8351G>A	p.Arg2784Gln	missense	Exon 19 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8351G>A	p.Arg2784Gln	missense	Exon 19 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7982G>A	p.Arg2661Gln	missense	Exon 19 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251422 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111676

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151862 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41312

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000269 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	3	1	Breast-ovarian cancer, familial, susceptibility to, 2 (6)
1	3	-	Hereditary cancer-predisposing syndrome (4)
3	1	-	not provided (4)
2	1	-	Hereditary breast ovarian cancer syndrome (3)
-	2	-	Familial cancer of breast (2)
-	1	-	BRCA2-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
-	1	-	Breast neoplasm (1)
-	1	-	Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.60	D
PhyloP100		9.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.90
MVP		0.95
MPC		0.17
ClinPred		0.99	D
GERP RS		5.3
gMVP		0.80
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80359076; hg19: chr13-32944558;