ENST00000530893.7:c.-56T>G

Variant names:

• chr13-32319323-T-G
• rs80358561
• ENST00000530893.7:c.-56T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The ENST00000530893.7(BRCA2):​c.-56T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,586 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 ENST00000530893.7 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.0003085
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 0.0210
• Publications: 10 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):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.22
• PP5: Variant 13-32319323-T-G is Pathogenic according to our data. Variant chr13-32319323-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 51406.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000530893.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.314T>G	p.Leu105*	stop_gained splice_region	Exon 3 of 27	NP_000050.3
	BRCA2	NM_001406722.1		c.-56T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 24	NP_001393651.1
	BRCA2	NM_001432077.1		c.314T>G	p.Leu105*	stop_gained splice_region	Exon 3 of 27	NP_001419006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000530893.7	TSL:1	c.-56T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 27	ENSP00000499438.2
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.314T>G	p.Leu105*	stop_gained splice_region	Exon 3 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.314T>G	p.Leu105*	stop_gained splice_region	Exon 3 of 27	ENSP00000439902.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459586 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726234

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110052

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (4)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Benign	0.14
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.26	N
PhyloP100		0.021
Vest4		0.83
GERP RS		-1.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.29
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: rs80358561; hg19: chr13-32893460; COSMIC: COSV66462153;