ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.145G>T (p.Glu49Ter) (rs80358435)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131868 SCV000186923 pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077257 SCV000146248 pathogenic Breast-ovarian cancer, familial 2 2005-01-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077257 SCV000146249 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131868 SCV000903685 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077257 SCV000326558 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077257 SCV000220745 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-26 criteria provided, single submitter literature only
Department of Medical Genetics,Oslo University Hospital RCV000077257 SCV000605677 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167820 SCV000591662 pathogenic Hereditary breast and ovarian cancer syndrome 2015-02-16 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077257 SCV000300300 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Fulgent Genetics,Fulgent Genetics RCV000515388 SCV000611177 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000043811 SCV000210431 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.145G>T at the cDNA level and p.Glu49Ter (E49X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. A minigene assay by Sanz et al. (2010) revealed skipping of exon 3 in a portion of transcripts, which would disrupt the PALB2 binding domain (Sanz 2010). Also reported as 373G>T using alternate nomenclature, the variant has been observed in several individuals with breast and/or ovarian cancer (Bergthorsson 2001, Llort 2002, Gallardo 2006, Vogel 2007, Weitzel 2013, de Juan 2015). We therefore consider BRCA2 Glu49Ter to be pathogenic.
GeneKor MSA RCV000238910 SCV000296807 pathogenic Familial cancer of breast 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000167820 SCV000694540 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.145G>T variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. However 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). The variant was not found in approximately 121100 control chromosomes. However, it has been reported in several HBOC patients/families in literature/clinical databases. Multiple clinical labs have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic.
Invitae RCV000167820 SCV000071824 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-06 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11389159, 20215541, 23479189, 24504028, 21120943). This variant is also known as 373G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 51129). Experimental studies have shown that this variant enhances skipping of exon 3, and results in an in-frame splicing isoform (p.Asp23_Leu105del) that removes the stop codon (PMID: 20215541). However, it also would disrupt an essential PALB2 binding domain and would likely still be deleterious (PMID: 21939546). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077257 SCV000296734 pathogenic Breast-ovarian cancer, familial 2 2015-02-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000043811 SCV000888980 pathogenic not provided 2015-02-10 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167820 SCV000587540 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077257 SCV000109054 pathogenic Breast-ovarian cancer, familial 2 2011-07-13 no assertion criteria provided clinical testing

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