ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4588A>T (p.Lys1530Ter) (rs80358692)

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Total submissions: 16
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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) RCV000077329 SCV000300769 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 RCV000044447 SCV000072460 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1530*) 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 with breast cancer (PMID: 26681312, 25452441). ClinVar contains an entry for this variant (Variation ID: 51678). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000212238 SCV000210339 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.4588A>T at the cDNA level and p.Lys1530Ter (K1530X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 4816A>T. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least one individual with breast cancer (Couch 2015). We consider BRCA2 Lys1530Ter to be pathogenic.
Ambry Genetics RCV000162921 SCV000213408 pathogenic Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing The p.K1530* pathogenic mutation (also known as c.4588A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4588. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer and in 1 breast cancer patient out of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Couch FJ et al. J Clin Oncol. 2015 Feb 1;33(4):304-11; ​Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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 RCV000077329 SCV000296632 pathogenic Breast-ovarian cancer, familial 2 2015-08-13 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077329 SCV000327057 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077329 SCV000488190 likely pathogenic Breast-ovarian cancer, familial 2 2016-01-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044447 SCV000605789 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Lys1530X variant in BRCA2 has been reported in at least 9 individuals with BRCA2-associated cancers (Susswein 2015, Couch 2015, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 1530, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ova rian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212238 SCV000889053 pathogenic not provided 2015-08-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162921 SCV000903414 pathogenic Hereditary cancer-predisposing syndrome 2020-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044447 SCV001442628 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4588A>T (p.Lys1530X) 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 was absent in 250310 control chromosomes (gnomAD). c.4588A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or prostate cancer (Couch_2015, Rebbeck_2018, Reimers_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic (8x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000077329 SCV001469050 pathogenic Breast-ovarian cancer, familial 2 2020-12-02 criteria provided, single submitter clinical testing This nonsense variant has been reported in multiple unrelated individuals affected with hereditary breast and ovarian cancer. It results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. This variant is absent in a large population database and has an entry in ClinVar. We consider c.4588A>T to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287825 SCV001474557 pathogenic none provided 2020-06-05 criteria provided, single submitter clinical testing The BRCA2 c.4588A>T; p.Lys1530Ter variant (rs80358692) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Couch 2015, Rebbeck 2018), and is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 66346). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620.
Sharing Clinical Reports Project (SCRP) RCV000077329 SCV000109126 pathogenic Breast-ovarian cancer, familial 2 2012-01-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077329 SCV000146454 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044447 SCV000587717 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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