13-32357901-G-T

Variant names:

• chr13-32357901-G-T
• rs587782028
• NM_000059.4:c.7777G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7777G>T​(p.Gly2593*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G2593G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.41
• Publications: 5 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32357901-G-T is Pathogenic according to our data. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357901-G-T is described in CliVar as Pathogenic. Clinvar id is 141811.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7777G>T	p.Gly2593*	stop_gained	Exon 16 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7777G>T	p.Gly2593*	stop_gained	Exon 16 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7408G>T	p.Gly2470*	stop_gained	Exon 16 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7777G>T		non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 27, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 16 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual who underwent genetic testing (PMID: 28152038). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jun 11, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G2593* pathogenic mutation (also known as c.7777G>T), located in coding exon 15 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7777. This changes the amino acid from a glycine to a stop codon within coding exon 15. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gly2593X variant has not been previously observed in the literature, nor has it been reported in the dbSNP, LOVD, Exome Variant Server, BIC or UMD databases. The alteration leads to a premature stop codon at position 2593 and is predicted to lead to a truncated or absent protein and loss of function, which is an established disease mechanism for the BRCA2 gene. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Apr 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141811). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly2593*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.4
Vest4		0.90
GERP RS		5.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587782028; hg19: chr13-32932038; COSMIC: COSV66455515;