13-32380043-C-T

Variant names:

• chr13-32380043-C-T
• rs45580035
• NM_000059.4:c.9154C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9154C>T​(p.Arg3052Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,782 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000073745: Experimental studies have shown that this missense change affects BRCA2 function (PMID:18451181, 18607349, 23108138, 25146914)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3052Q) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:38 U:1
• Conservation: PhyloP100: 2.98
• Publications: 90 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073745: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 18607349, 23108138, 25146914).; SCV000918902: The most pronounced variant effect results in <10% of normal activity (Farrugia_2008, Kuznetsov_2008, Walker_2010).; SCV003932774: Functional analyses of this variant are published (PMID: 18451181, 23108138, 25146914, 18607349) describing it as deleterious.; SCV000213515: "Additionally, several functional studies have found this alteration to be pathogenic (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81; Hendriks G et al. Hum. Mutat., 2014 Nov;35:1382-91; Guidugli L et al. Am. J. Hum. Genet., 2018 Jan; Mesman RLS et al. Genet Med 2019 02;21(2):293-302; Richardson ME at al. Am J Hum Genet 2021 03;108(3):458-468 )."; SCV000537644: Functional studies have shown that the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920).; SCV005901862: This variant was reported by three calibrated studies to affect protein function similar to pathogenic control variants (PMID: 29988080, 33609447, 32444794) (PS3).; SCV000279425: Published functional studies demonstrate a damaging effect: impaired homology directed repair activity and cell survival, and increased sensitivity to PARP inhibitors (Farrugia et al., 2008; Kuznetsov et al., 2008; Guidugli et al., 2013; Cunningham et al., 2014; Hendriks et al., 2014; Shimelis et al., 2017; Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020); SCV000296544: Functional studies in the published literature demonstrate that this variant is damaging to BRCA2 protein function (PMID: 29394989 (2018), 28283652 (2017), 25146914 (2014), 18607349 (2008), 18451181 (2008)).; SCV005877084: Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. Kuznetsov SG et al. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008 Aug;14(8):875-81.; SCV000693592: Experimental studies have shown that this missense change results in the loss of DNA repair activity of the encoded protein product in vitro (PMID: 18451181,PMID: 18607349).; SCV001551438: Functional studies investigating the DNA break repair activity of p.Arg3052Trw showed reduced activity of this variant (Farrugia 2008, Guidugli 2013). A study using mouse embryonic stem cells and bacterial artificial chromosomes demonstrated that cells expressing p.Arg3052Trw did not survive, suggesting it to be deleterious (Borg 2010).; SCV004846128: Functional studies have shown that the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32380044-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 462517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 13-32380043-C-T is Pathogenic according to our data. Variant chr13-32380043-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 52763.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.9154C>T	p.Arg3052Trp	missense	Exon 24 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9154C>T	p.Arg3052Trp	missense	Exon 24 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9103C>T	p.Arg3035Trp	missense	Exon 24 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.9154C>T	p.Arg3052Trp	missense	Exon 24 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9154C>T	p.Arg3052Trp	missense	Exon 24 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8785C>T	p.Arg2929Trp	missense	Exon 24 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251190 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000247 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (14)
9	-	-	not provided (9)
6	-	-	Hereditary breast ovarian cancer syndrome (6)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Familial cancer of breast (2)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.60	D
PhyloP100		3.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.76
MutPred		0.92		Gain of catalytic residue at R3052 (P = 0.0416)
MVP		0.96
MPC		0.17
ClinPred		0.95	D
GERP RS		1.4
gMVP		0.86
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs45580035; hg19: chr13-32954180;