13-32319154-G-T

Position:

• chr13-32319154-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.145G>T​(p.Glu49*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,722 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. E49E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 3.75

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 13-32319154-G-T is Pathogenic according to our data. Variant chr13-32319154-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 51129.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319154-G-T is described in Lovd as [Pathogenic]. Variant chr13-32319154-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.145G>T	p.Glu49*	stop_gained	3/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.145G>T	p.Glu49*	stop_gained	3/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-225G>T		5_prime_UTR_variant	3/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.145G>T		non_coding_transcript_exon_variant	2/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
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	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant changes 1 nucleotide in exon 3 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 reported in at least five individuals affected with breast or ovarian cancer (PMID: 20927582, 23479189, 24504028, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000017) and has been identified in 54 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/251328 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. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 26, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 13, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jan 26, 2005	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 28, 2024	The BRCA2 c.145G>T (p.Glu49*) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals and families affected with breast or ovarian cancer (PMIDs: 33471991 (2021), 30287823 (2018), 29446198 (2018), 11857748 (2002), 11389159 (2001)), and it has been reported to cause exon 3 skipping and loss of the essential PALB2 binding domain of BRCA2 (PMID 20215541 (2010)). The frequency of this variant in the general population, 0.000004 (1/251328 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	GeneDx	Sep 05, 2023	Nonsense variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Sanz et al., 2010); Observed in individuals with a personal and family history of breast and/or ovarian cancer (Bergthorsson et al., 2001; Llort et al., 2002; Gallardo et al., 2006; Vogel et al., 2007; Weitzel et al., 2013; de Juan et al., 2015); Not observed at 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 373G>T; This variant is associated with the following publications: (PMID: 16261400, 20033483, 20927582, 28680148, 29922827, 11389159, 26681312, 24504028, 23479189, 26026974, 25639900, 25628955, 24123850, 28127413, 23233716, 11857748, 16284991, 17925560, 21913181, 29088781, 20215541, 18465347, 26295337, 21939546, 21120943, 29084914, 29983698, 30287823, 29446198, 30720243, 31454914, 31432501, 32341426, 32719484, 30787465, 31589614, 33754277, 33804961) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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	Feb 21, 2022	Variant summary: BRCA2 c.145G>T (p.Glu49X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 251328 control chromosomes (gnomAD). c.145G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Bergthorsson_2001, Vogel_2007, Alvarez_2017). These data indicate that the variant is very likely to be associated with disease. Functional studies indicate that this nonsense variant abrogates ESE binding site and causes deletion of 82 amino acid residues essential for PALB2 binding. The effect of alternative splicing can be described as p.Asp23Leu105del (Sanz_2010). 12 ClinVar submitters, including one expert panel (ENIGMA) and one consortium (CIMBA), have assessed this variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Glu49*) 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 (rs80358435, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11389159, 20215541, 21120943, 23479189, 24504028). This variant is also known as 373G>T. ClinVar contains an entry for this variant (Variation ID: 51129). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 29, 2023	This variant changes 1 nucleotide in exon 3 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 reported in at least five individuals affected with breast or ovarian cancer (PMID: 20927582, 23479189, 24504028, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000017) and has been identified in 54 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/251328 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 29, 2022	The p.E49* pathogenic mutation (also known as c.145G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 145. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been reported in multiple breast and/or ovarian cancer kindreds to date (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Vogel KJ et al. J. Clin. Oncol. 2007 Oct;25:4635-41; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Labidi-Galy S et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). Haplotype analysis has identified this alteration as a Chilean founder mutation (Alvarez C et al. Oncotarget. 2017 Sep;8:74233-74243). Of note, this alteration is also designated as 373G>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a single base change resulting in the substitution of the glutamic acid at amino acid position 49 of the BRCA2 protein by a stop codon, thus resulting in a truncated protein product. This variant has previously been reported as a pathogenic mutation in the BIC database (http://research.nhgri.nih.gov/bic). -

Medulloblastoma;C0040588:Tracheoesophageal fistula;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

May 18, 2017

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu49X variant was identified in 6 of 3372 proband chromosomes (frequency: 0.002) from Hispanic and/or American, and Spanish individuals or families with breast and ovarian cancers (Pal 2005, Vogel 2007, de Juan Jimenez 2013); however, control chromosomes were not evaluated in these studies. In a study using splice site assays (lymphocyte reverse transcriptase PCR and/or hybrid minigene in HeLa and nontumour breast epithelial cells), the variant induced exon 3 skipping, indicating the splicing regulatory elements were altered, in agreement with the in-silico prediction model for splicing (Sanz 2010). The variant was also identified in dbSNP (ID: rs80358435) “With pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Glu49X variant was also identified in HGMD, LOVD, COSMIC, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, as pathogenic by BIC, as pathogenic by Ambry Genetics, and no classification provided by Invitae), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), the BIC database (20X with pathogenic clinical importance), and UMD (20X as a 5-Causal variant). The p.Glu49X variant leads to a premature stop codon at position 49 of the polypeptide, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.72
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80358435; hg19: chr13-32893291;