13-32338277-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.3922G>T(p.Glu1308Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000702 in 1,566,908 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 0.718

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32338277-G-T is Pathogenic according to our data. Variant chr13-32338277-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 37867.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338277-G-T is described in Lovd as [Pathogenic]. Variant chr13-32338277-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3922G>T	p.Glu1308Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3922G>T	p.Glu1308Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1414798 Hom.: 0 Cov.: 34 AF XY: 0.00000428 AC XY: 3 AN XY: 700622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000566

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000869

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Feb 25, 2020	The c.3922G>T variant in the BRCA2 gene is a is a single base pair substitution at nucleotide 3922 in exon 11 of 27 of the gene, resulting in a premature truncation of the protein at amino acid 1308 of 3419 (p.Glu1308Ter), and is expected to cause nonsense mediated mRNA decay. This variant has been observed in the GenomeAggregationDatabase (gnomAD) at a very low frequency (1/31,390), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in individuals with a personal and family history of early-onset breast and ovarian cancer (including PMIDs: 12655567, 17925560, 19241424, 12955716, 23479189, 28724667) male breast cancer (PMIDs: 26026974, 28008555, 31892343), prostate cancer (PMID: 27433846) as well as pancreatic cancer (PMID: 24737347). This variant has also been seen in the compound heterozygous state in an individual with autosomal recessive Fanconi anemia (PMIDs: 14559878) and an individual with pediatric myelodysplastic syndrome (PMID: 29146900). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 14, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 27, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	Reported in several individuals with a personal or family history of breast and/or ovarian cancer and is considered a recurrent variant in Hispanic individuals (Vogel 2007, Dutil 2012, de Juan Jimenez 2013); Observed with a pathogenic BRCA2 variant on the opposite allele (in trans) in a child with Fanconi anemia (Offit 2003); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4150G>T; This variant is associated with the following publications: (PMID: 23479189, 12955716, 28127413, 28008555, 29446198, 25525159, 19241424, 17925560, 22682623, 24737347, 12655567, 26681312, 20609467, 26564481, 14684619, 26064523, 26543556, 28477318, 26026974, 27433846, 25085752, 26556299, 28724667, 28993434, 30720243, 30702160, 31589614, 31825140, 32719484, 33084842, 30787465, 14559878) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2023	The BRCA2 c.3922G>T (p.Glu1308*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28993434 (2018), 28477318 (2017), 28724667 (2017)), prostate cancer (PMID: 27433846 (2016)), and pancreatic cancer (PMID: 24737347 (2014)). The frequency of this variant in the general population, 0.000032 (1/31390 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	Variant summary: The BRCA2 c.3922G>T (p.Glu1308X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3967A>T/p.Lys1323X, c.4222C>T/p.Gln1408X). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous breast cancer patients and is absent in 88146 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Glu1308*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80358638, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12655567, 12955716, 14559878, 20033483, 22682623, 23479189, 27433846, 28008555). This variant is also known as 4150G>T. ClinVar contains an entry for this variant (Variation ID: 37867). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2023	The c.3922G>T (p.E1308*) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a G to T substitution at nucleotide position 3922. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 1308. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ Based on the available evidence, the BRCA2 c.3922G>T (p.E1308*) alteration is classified as pathogenic. However, because this variant is identified in one or more patients with Fanconi anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (1/31390) total alleles studied. The highest observed frequency was 0.118% (1/846) of Latino alleles. This mutation has been reported in several individuals with personal and/or family histories of breast, ovarian, and/or prostate cancer (Duran, 2003; Hall, 2009; Pritchard, 2016; Gabaldó Barrios, 2017; Wen, 2018). This mutation has also been reported as a BRCA2 compound heterozygous finding in a child diagnosed with a medulloblastoma at 3.5 years of age and Fanconi anemia (Offit, 2003). Of note, this alteration is also designated as 4150G>T in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2021	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer (PMID: 12655567, 12955716, 19241424, 20033483, 21508395, 22682623, 23479189, 26026974, 26543556, 28008555, 28724667, 28993434, 33471991), including an individual affected with bilateral breast cancer and pancreatic cancer (PMID: 21508395). This variant also has been reported in one individual each affected with prostate and pancreatic cancer (PMID: 24737347, 27433846). This variant has been reported in trans with a second pathogenic BRCA2 mutation (p.Gln3066*) in an individual affected with the recessive disease Fanconi anemia (PMID: 14559878). This variant has been identified in 1/31390 chromosomes 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The BRCA2 c.3922G>T variant is predicted to result in premature protein termination (p.Glu1308*). This variant is also known as c.4150G>T using alternate nomenclature. This variant has been reported to be causative for hereditary breast and ovarian cancer in several patients (see for example - de Juan et al. 2015. PubMed ID: 26026974; Duran et al. 2003. PubMed ID: 12655567; de Juan et al. 2013 PubMed ID: 23479189) and was also reported in a patient with Fanconi anemia who was compound heterozygous for p.Glu1308* and p.Gln3066* (Offit et al. 2003. PubMed ID: 14559878). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD; however, this frequency is considered unreliable due to the relatively few number of individuals covered at this position. In ClinVar this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37867/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		3.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358638; hg19: chr13-32912414;