13-32319154-G-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.145G>T | p.Glu49* | stop_gained | Exon 3 of 27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.145G>T | p.Glu49* | stop_gained | Exon 3 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000614259.2 | n.145G>T | non_coding_transcript_exon_variant | Exon 2 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000530893.7 | c.-225G>T | 5_prime_UTR_variant | Exon 3 of 27 | 1 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251328 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461722Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727166 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10
Variant allele predicted to encode a truncated non-functional protein.
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.
PVS1; PM5_PTC_Strong
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
not provided Pathogenic:7
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.
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)
Hereditary breast ovarian cancer syndrome Pathogenic:3
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.
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 (internal data). For these reasons, this variant has been classified as Pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:2
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.
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
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:Esophageal atresia/tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Prostate cancer;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
Gastric cancer Pathogenic:1
Malignant tumor of breast Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at