13-32362692-A-G

Variant names:

• chr13-32362692-A-G
• rs80359026
• NM_000059.4:c.7975A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7975A>G​(p.Arg2659Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000661425: Both of these alterations are also non-functional in protein-based homology-directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75).; SCV006060950: Functional studies have shown that this variant impacts BRCA2 function in a homology-directed repair assay and increases sensitivity to PARP inhibitors in mammalian cells (PMID:23108138, 29394989, 32444794). RNA studies using patient-derived RNA and minigene assays have shown this variant causes partial in-frame skipping of exon 17 (PMID:22505045, 28339459, 28905878, 31191615).; SCV000568488: "Protein-based functional studies demonstrate a damaging effect: impaired homology-directed repair activity and sensitivity to PARP inhibitors (Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020; Iversen et al., 2022)"; SCV002049730: Functional assays of homology-directed repair suggest the variant protein has significantly reduced activity (Guidugli 2013).; SCV005625303: Functional studies demonstrated that this variant resulted in partial in frame skipping of exon 17 (PMIDs: 21120943 (2011) and 28339459 (2017)), as well as reduced activity in a homology-directed DNA repair (HDR) assay (PMID:24323938 (2014)).; SCV001516845: Experimental studies have shown that this missense change affects BRCA2 function (PMID:15695382, 23108138, 29884841).; SCV006311069: Experimental studies have shown that this missense change affects BRCA2 function (PMID:15695382, 23108138, 29884841).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2659T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:3
• Conservation: PhyloP100: 5.92
• Publications: 25 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000661425: Both of these alterations are also non-functional in protein-based homology-directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75).; SCV006060950: Functional studies have shown that this variant impacts BRCA2 function in a homology-directed repair assay and increases sensitivity to PARP inhibitors in mammalian cells (PMID: 23108138, 29394989, 32444794). RNA studies using patient-derived RNA and minigene assays have shown this variant causes partial in-frame skipping of exon 17 (PMID: 22505045, 28339459, 28905878, 31191615).; SCV000568488: "Protein-based functional studies demonstrate a damaging effect: impaired homology-directed repair activity and sensitivity to PARP inhibitors (Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020; Iversen et al., 2022)"; SCV002049730: Functional assays of homology-directed repair suggest the variant protein has significantly reduced activity (Guidugli 2013).; SCV005625303: Functional studies demonstrated that this variant resulted in partial in frame skipping of exon 17 (PMIDs: 21120943 (2011) and 28339459 (2017)), as well as reduced activity in a homology-directed DNA repair (HDR) assay (PMID: 24323938 (2014)).; SCV001516845: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 15695382, 23108138, 29884841).; SCV006311069: Experimental studies have shown that this missense change affects BRCA2 function (PMID:15695382, 23108138, 29884841).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 30 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32362693-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 52455.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32362692-A-G is Pathogenic according to our data. Variant chr13-32362692-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 38130.Status of the report is reviewed_by_expert_panel, 3 stars.

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.7975A>G	p.Arg2659Gly	missense splice_region	Exon 17 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7975A>G	p.Arg2659Gly	missense splice_region	Exon 17 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7975A>G	p.Arg2659Gly	missense splice_region	Exon 17 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.7975A>G	p.Arg2659Gly	missense splice_region	Exon 17 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7975A>G	p.Arg2659Gly	missense splice_region	Exon 17 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7606A>G	p.Arg2536Gly	missense splice_region	Exon 17 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	3	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
4	-	-	not provided (4)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Vest4		0.85
MutPred		0.78		Loss of MoRF binding (P = 0.0132)
MVP		0.97
MPC		0.18
ClinPred		0.99	D
GERP RS		4.5
gMVP		0.89
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.51		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359026; hg19: chr13-32936829;