ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8991T>G (p.Tyr2997Ter)

dbSNP: rs397508028
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Total submissions: 8
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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) RCV000257890 SCV000324725 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257890 SCV000328021 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657636 SCV000779380 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8991T>G at the cDNA level and p.Tyr2997Ter (Y2997X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as BRCA2 9219T>G using alternate nomenclature, has been reported in families with breast and/or ovarian cancer (Ahn 2007, Son 2012, Kim 2012, Kang 2015, Eoh 2017) and is considered pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000771470 SCV000903913 pathogenic Hereditary cancer-predisposing syndrome 2021-08-05 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 23 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 detected in at least two individuals affected with breast cancer and an individual affected with ovarian cancer (PMID: 16455195, 29020732, 33471991; Leiden Open Variation Database DB-ID BRCA2_005517). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001388610 SCV001589675 pathogenic Hereditary breast ovarian cancer syndrome 2023-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr2997*) 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16455195, 29020732). ClinVar contains an entry for this variant (Variation ID: 52722). 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 RCV000771470 SCV002682153 pathogenic Hereditary cancer-predisposing syndrome 2024-05-10 criteria provided, single submitter clinical testing The p.Y2997* pathogenic mutation (also known as c.8991T>G), located in coding exon 22 of the BRCA2 gene, results from a T to G substitution at nucleotide position 8991. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation has been described multiple times in Korean HBOC patients (Ahn SH et al. Cancer Lett. 2007 Jan;245:90-5; Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52; Eoh KJ et al. Cancer Res. Treat. 2018 Jul;50:917-925). Of note, this alteration is also designated as 9219T>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657636 SCV002774324 pathogenic not provided 2021-08-24 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer or ovarian cancer in the published literature (PMID: 16455195 (2007) and 29020732 (2018)). Based on the available information, this variant is classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000657636 SCV001552429 uncertain significance not provided no assertion criteria provided clinical testing

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