ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3922G>T (p.Glu1308Ter)

gnomAD frequency: 0.00006  dbSNP: rs80358638
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Total submissions: 22
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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) RCV000031448 SCV000300685 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.
Invitae RCV000167856 SCV000072325 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1308*) 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 (rs80358638, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12655567, 12955716, 14559878, 20033483, 22682623, 23479189, 27433846, 28008555). This variant is also known as 4150G>T. ClinVar contains an entry for this variant (Variation ID: 37867). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000128952 SCV000172830 pathogenic Hereditary cancer-predisposing syndrome 2021-09-02 criteria provided, single submitter clinical testing The p.E1308* pathogenic mutation (also known as c.3922G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 3922. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This mutation has been reported in several individuals with personal and/or family histories of breast, ovarian, and/or prostate cancer (Duran M et al. Hum. Mutat. 2003 Apr;21:448; Hall MJ et al. Cancer. 2009 May;115:2222-33; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Gabaldó Barrios X et al. Fam. Cancer. 2017 Oct;16:477-489; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103). This mutation has also been reported as a BRCA2 compound heterozygous finding in a child diagnosed with a medulloblastoma at 3.5 years of age and Fanconi Anemia (Offit K et al. J. Natl. Cancer Inst. 2003 Oct;95:1548-51). Of note, this alteration is also designated as 4150G>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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx RCV000044312 SCV000210325 pathogenic not provided 2019-11-20 criteria provided, single submitter clinical testing Reported in several individuals with a personal or family history of breast and/or ovarian cancer and is considered a recurrent variant in Hispanic individuals (Vogel 2007, Dutil 2012, de Juan Jimenez 2013); Observed with a pathogenic BRCA2 variant on the opposite allele (in trans) in a child with Fanconi anemia (Offit 2003); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a 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 4150G>T; This variant is associated with the following publications: (PMID: 23479189, 12955716, 28127413, 28008555, 29446198, 25525159, 19241424, 17925560, 22682623, 24737347, 12655567, 26681312, 20609467, 26564481, 14684619, 26064523, 26543556, 28477318, 26026974, 27433846, 25085752, 26556299, 28724667, 28993434, 30720243, 30702160, 31589614, 31825140, 32719484, 33084842, 30787465, 14559878)
Eurofins Ntd Llc (ga) RCV000044312 SCV000225189 pathogenic not provided 2015-07-06 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000128952 SCV000292135 pathogenic Hereditary cancer-predisposing syndrome 2021-04-06 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer (PMID: 12655567, 12955716, 19241424, 20033483, 21508395, 22682623, 23479189, 26026974, 26543556, 28008555, 28724667, 28993434, 33471991), including an individual affected with bilateral breast cancer and pancreatic cancer (PMID: 21508395). This variant also has been reported in one individual each affected with prostate and pancreatic cancer (PMID: 24737347, 27433846). This variant has been reported in trans with a second pathogenic BRCA2 mutation (p.Gln3066*) in an individual affected with the recessive disease Fanconi anemia (PMID: 14559878). This variant has been identified in 1/31390 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044312 SCV000296714 pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing The BRCA2 c.3922G>T (p.Glu1308*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28993434 (2018), 28477318 (2017), 28724667 (2017)), prostate cancer (PMID: 27433846 (2016)), and pancreatic cancer (PMID: 24737347 (2014)). The frequency of this variant in the general population, 0.000032 (1/31390 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031448 SCV000326942 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031448 SCV000488095 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-12-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000465243 SCV000541012 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genologica Medica RCV000031448 SCV000577953 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167856 SCV000694731 pathogenic Hereditary breast ovarian cancer syndrome 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3922G>T (p.Glu1308X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.3967A>T/p.Lys1323X, c.4222C>T/p.Gln1408X). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous breast cancer patients and is absent in 88146 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Revvity Omics, Revvity Omics RCV000044312 SCV002024778 pathogenic not provided 2023-08-31 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000128952 SCV002533837 pathogenic Hereditary cancer-predisposing syndrome 2021-06-13 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002490436 SCV002798690 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 2021-09-27 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031448 SCV004032296 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-08-14 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PM2_SUP
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV000031448 SCV004037355 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2020-02-25 criteria provided, single submitter clinical testing The c.3922G>T variant in the BRCA2 gene is a is a single base pair substitution at nucleotide 3922 in exon 11 of 27 of the gene, resulting in a premature truncation of the protein at amino acid 1308 of 3419 (p.Glu1308Ter), and is expected to cause nonsense mediated mRNA decay. This variant has been observed in the GenomeAggregationDatabase (gnomAD) at a very low frequency (1/31,390), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in individuals with a personal and family history of early-onset breast and ovarian cancer (including PMIDs: 12655567, 17925560, 19241424, 12955716, 23479189, 28724667) male breast cancer (PMIDs: 26026974, 28008555, 31892343), prostate cancer (PMID: 27433846) as well as pancreatic cancer (PMID: 24737347). This variant has also been seen in the compound heterozygous state in an individual with autosomal recessive Fanconi anemia (PMIDs: 14559878) and an individual with pediatric myelodysplastic syndrome (PMID: 29146900).
Sharing Clinical Reports Project (SCRP) RCV000031448 SCV000054053 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-07-27 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031448 SCV000146336 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000031448 SCV000207341 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2014-11-06 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000167856 SCV000587691 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
GenomeConnect, ClinGen RCV000167856 SCV002074856 not provided Hereditary breast ovarian cancer syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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