13-32398438-G-T

Variant names:

• chr13-32398438-G-T
• rs80359251
• NM_000059.4:c.9925G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID:29988080) and pathogenic control variants (PMID:18607349) (PS3 and BS3 not met).In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA026335/MONDO:0012933/097

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:7
• Conservation: PhyloP100: 0.810
• Publications: 18 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

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.9925G>T	p.Glu3309*	stop_gained	Exon 27 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9925G>T	p.Glu3309*	stop_gained	Exon 27 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9874G>T	p.Glu3292*	stop_gained	Exon 27 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.9925G>T	p.Glu3309*	stop_gained	Exon 27 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9925G>T	p.Glu3309*	stop_gained	Exon 27 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.9556G>T	p.Glu3186*	stop_gained	Exon 27 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

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

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.000179 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
-	2	-	BRCA2-related cancer predisposition (2)
1	1	-	Hereditary breast ovarian cancer syndrome (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.14	N
PhyloP100		0.81
Vest4		0.64
GERP RS		2.5
Mutation Taster		=6/194	disease causing (fs/PTC)

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: rs80359251; hg19: chr13-32972575;