13-32370420-C-T

Variant names:

• chr13-32370420-C-T
• rs80359075
• NM_000059.4:c.8350C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8350C>T​(p.Arg2784Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,730 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006555856: Functional studies show reduced homology-directed DNA repair, indicating that this variant impacts protein function (Farrugia DJ et al., PMID:18451181" 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: 0.0000041 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 U:5
• Conservation: PhyloP100: 4.25
• Publications: 29 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006555856: Functional studies show reduced homology-directed DNA repair, indicating that this variant impacts protein function (Farrugia DJ et al., PMID: 18451181; Guidugli L et al., PMID: 2310813).; SCV000073500: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 23108138, 29884841, 29988080, 33293522).; SCV001363256: "significantly impaired homology directed repair activity meaured by HDR assays." PMID:18451181, PMID:29394989, PMID:25782689; SCV001478299: "In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong)."; SCV000186727: Internal structural analysis indicates that this variant is likely to disrupt BRCA2 binding to DSS1, a protein that has been shown to stabilize BRCA2 and participate in its clinically relevant functions (Ambry internal data; Yang, 2002). Several independent assays find this variant non-functional including multiple homology-directed DNA repair assays; a centriole amplification assay and a mouse embryonic stem cell complementation assay (Farrugia, 2008; Guidugli, 2013; Guidugli, 2018; Mesman, 2018).; SCV000911858: Functional studies have shown the mutant protein to be non-functional in homology-directed DNA repair activity (PMID: 18451181, 29394989, 29988080, 33609447, 35736817) and unable to complement BRCA2-deficiency in mouse embryonic stem cells (PMID: 29988080).; SCV000329141: "Published functional studies demonstrate a damaging effect: displayed reduced homologous recombination repair activity in multiple homology-directed DNA break repair assays as well as poor survival in mouse embryonic stem cell assay (PMID: 18451181, 23108138, 29988080, 29884841, 33293522, 35736817)"; SCV001133931: Functional evidence suggests that this variant may impact protein function (PMIDs: 33609447 (2022), 33293522 (2020), 29394989 (2018), 29988080 (2018), 24323938 (2014), 23108138 (2013), 18451181 (2008)).; SCV003799562: Functional analyses of the variant protein show impaired homology-directed DNA break repair activity (Farrugia 2008, Guidugli 2013, Hart 2019, Mesman 2019).; SCV004118990: Experimental studies have demonstrated that this variant reduces homology-directed DNA repair (HRD) (Table 2, Guidugli et al. 2013. PubMed ID: 23108138; Farrugia et al. 2008. PubMed ID: 18451181; Guidugli et al. 2018. PubMed ID: 29394989; Mesman et al. 2019. PubMed ID: 29988080).; SCV005417890: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• 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, 0.81
• PP5: Variant 13-32370420-C-T is Pathogenic according to our data. Variant chr13-32370420-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.8350C>T	p.Arg2784Trp	missense	Exon 19 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8350C>T	p.Arg2784Trp	missense	Exon 19 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8350C>T	p.Arg2784Trp	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.8350C>T	p.Arg2784Trp	missense	Exon 19 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8350C>T	p.Arg2784Trp	missense	Exon 19 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7981C>T	p.Arg2661Trp	missense	Exon 19 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251430 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727076

African (AFR) AF: 0.00 AC: 0 AN: 33470

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

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: 0.00000180 AC: 2 AN: 1111646

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	2	-	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
6	1	-	not provided (7)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	BRCA2-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
-	1	-	Chordoma (1)
1	-	-	Familial cancer of breast (1)
-	1	-	Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 (1)
1	-	-	Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.75	D
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.67
MVP		0.96
MPC		0.17
ClinPred		1.0	D
GERP RS		4.5
gMVP		0.86
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.020		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: rs80359075; hg19: chr13-32944557; COSMIC: COSV66449232; COSMIC: COSV66449232;