13-32394803-A-T

Variant names:

• chr13-32394803-A-T
• rs28897759
• NM_000059.4:c.9371A>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9371A>T​(p.Asn3124Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,530 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: "SCV000073815: Experimental studies have shown that this missense change affects BRCA2 function (PMID:22678057, 23108138)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3124K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:42 U:1
• Conservation: PhyloP100: 6.06
• Publications: 65 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073815: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 22678057, 23108138).; SCV000695235: Functional studies show the variant to disrupts BRCA2 homology-directed DNA break repair activity, and that it is unable to rescue the phenotype in BRCA2 null (Guidugli_2012, Biswas_2012, Ikegami_2020).; SCV001478280: The variant has a probability of pathogenicity of 1.0 (PS3_strong). Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). Corrected and simplified output based on instructions: "The variant has a probability of pathogenicity of 1.0 (PS3_strong)."; SCV000185187: This alteration has been predicted to be pathogenic based on cell-based functional assays (Biswas K et al. Hum. Mol. Genet. 2012 Sep;21:3993-4006; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75).; SCV000684058: Functional studies have shown that the variant impacts BRCA2 activities in homology-directed DNA repair assays (PMID: 22678057, 23108138, 29394989, 29988080, 33609447, 35736817), in sensitivity assays to PARP inhibitors, cisplatin and carboplatin (PMID: 32444794, 37922907) and in a haploid cell proliferation assay (PMID: 39779857).; SCV000278888: Published functional studies demonstrate a damaging effect: defective homology-directed DNA break repair, impaired protein structure and stability, and sensitivity to PARP inhibitors (PMID: 22678057, 23108138, 29394989, 29884841, 32444794, 33964450, 33609447, 35736817); SCV000600859: "In addition, functional studies in the published literature demonstrate that this variant is damaging to BRCA2 protein function (PMID: 32444794 (2020), 23108138 (2013), 22678057 (2012), and 22729890 (2012))."; SCV000592279: In vitro functional studies showed the p.Asn3124Ile variant compromised BRCA2 function (Biswas 2012, Guidugli 2013).; SCV004846161: Functional studies have shown that this variant results in the loss of homology-directed repair activity of the BRCA2 protein (PMID: 22678057, 23108138, 29394989, 29988080, 33609447, 33964450).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 35 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 chr13-32394804-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 462524.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 13-32394803-A-T is Pathogenic according to our data. Variant chr13-32394803-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 38233.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.9371A>T	p.Asn3124Ile	missense	Exon 25 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9371A>T	p.Asn3124Ile	missense	Exon 25 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9320A>T	p.Asn3107Ile	missense	Exon 25 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.9371A>T	p.Asn3124Ile	missense	Exon 25 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9371A>T	p.Asn3124Ile	missense	Exon 25 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.9002A>T	p.Asn3001Ile	missense	Exon 25 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151714 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251346 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

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: 39682

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

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

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151714 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74022

African (AFR) AF: 0.00 AC: 0 AN: 41268

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
14	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (15)
13	-	-	not provided (13)
4	-	-	Familial cancer of breast (4)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
2	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.89	D
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MutPred		0.86		Loss of disorder (P = 0.0481)
MVP		0.98
MPC		0.18
ClinPred		0.99	D
GERP RS		5.9
gMVP		0.76
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs28897759; hg19: chr13-32968940; COSMIC: COSV105932290;