ClinVar Miner

Submissions for variant NM_000059.4(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
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.
Invitae RCV000167820 SCV000071824 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 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. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11389159, 20215541, 23479189, 24504028, 21120943). This variant is also known as 373G>T. 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131868 SCV000186923 pathogenic Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing 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.
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.
Counsyl RCV000077257 SCV000220745 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-26 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077257 SCV000296734 pathogenic Breast-ovarian cancer, familial 2 2015-02-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000238910 SCV000296807 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing 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).
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
Department of Medical Genetics, Oslo University Hospital RCV000077257 SCV000605677 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000043811 SCV000888980 pathogenic not provided 2019-11-27 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Color Health, Inc RCV000131868 SCV000903685 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077257 SCV000109054 pathogenic Breast-ovarian cancer, familial 2 2011-07-13 no assertion criteria provided clinical testing
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
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353561 SCV000591662 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing 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.

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