Submissions for variant NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter)

dbSNP: rs80358435

Total submissions: 27

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, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167820	SCV000071824	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	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 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.
Ambry Genetics	RCV000131868	SCV000186923	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-29	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	2023-09-05	criteria provided, single submitter	clinical testing	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)
Counsyl	RCV000077257	SCV000220745	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-26	criteria provided, single submitter	literature only
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, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077257	SCV000605677	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 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 ovarian cancer syndrome	2022-02-21	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000043811	SCV000888980	pathogenic	not provided	2019-11-27	criteria provided, single submitter	clinical testing	This variant causes the premature termination of BRCA2 protein synthesis. In addition, this variant has been described in individuals and families affected with breast or ovarian cancer in the published literature (PMID: 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)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131868	SCV000903685	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000043811	SCV002023618	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043811	SCV004027389	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000238910	SCV004210427	pathogenic	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077257	SCV004846378	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077257	SCV005045983	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000043811	SCV005199767	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077257	SCV000109054	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-07-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077257	SCV000146248	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2005-01-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077257	SCV000146249	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000043811	SCV001743012	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000043811	SCV001952845	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162367	SCV002758117	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077257	SCV004243637	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing