ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5864C>A (p.Ser1955Ter) (rs80358815)

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Total submissions: 20
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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) RCV000077364 SCV000282416 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044777 SCV000072790 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.Ser1955*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80358815, ExAC 0.002%). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 11802209, 15131399, 16683254, 24504028, 24728189, 26586665), as well as prostate cancer and pancreatic cancer (PMID: 26483394, 27433846). This variant is also known as 6092C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 51954). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162927 SCV000213414 pathogenic Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing The p.S1955* pathogenic mutation (also known as c.5864C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5864. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in multiple high-risk breast and/or ovarian cancer kindreds (Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). It has also been reported in a patient with epithelial ovarian cancer and a patient with metastatic prostate cancer, both of whom were unselected for family history of cancer or age at diagnosis (Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53). Of note, this alteration is also designated as S1955X and 6092C>A 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.
Counsyl RCV000077364 SCV000220841 likely pathogenic Breast-ovarian cancer, familial 2 2014-10-28 criteria provided, single submitter literature only
GeneDx RCV000221022 SCV000278865 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5864C>A at the cDNA level and p.Ser1955Ter (S1955X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 6092C>A. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>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 breast, ovarian, and prostate cancer patients (Meindl 2002, Lubinski 2004, Cunningham 2014, Pritchard 2016, Barnes 2017). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221022 SCV000296595 pathogenic not provided 2020-04-27 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077364 SCV000327303 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044777 SCV000588105 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505916 SCV000602868 pathogenic not specified 2017-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044777 SCV000694908 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5864C>A (p.Ser1955X) 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.5909C>A/p.S1970X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/124064 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Variant was found to co-segregate in multiple HBOC families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077364 SCV000743314 pathogenic Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162927 SCV000903519 pathogenic Hereditary cancer-predisposing syndrome 2020-10-26 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 individuals affected with breast or ovarian cancer (PMID: 11802209, 12928470, 15131399, 16683254, 24504028, 24728189, 26483394, 2832422), prostate cancer (PMID: 27433846), and pancreatic cancer (PMID: 26483394). This variant has been identified in 4/282358 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000221022 SCV001501474 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077364 SCV000109161 pathogenic Breast-ovarian cancer, familial 2 2012-07-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077364 SCV000146718 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 RCV000044777 SCV000587807 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353854 SCV000592009 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser1955X variant was identified in 3 of 4656 proband chromosomes (frequency: 0.001) from German and multiethnic cohorts of individuals or families with ovarian and breast/other cancers (Meindl 2002, Lubinski 2004). In a study correlating mutation locus to disease risk in BRCA2 positive patients, Lubinski (2004) found that mutations falling within BIC 3035-6629, considered the OCCR (ovarian cancer cluster region), had increased risk of ovarian cancer and decreased risk of breast and prostate cancers compared to nonOCCR regions. In another study assessing HRD (homologous recombination deficiency) in ovarian cancer patients unselected for family history, it was found that patients with germline or somatic mutations in BRCA1, BRCA2 or RAD51C, were likely to have high grade serous tumors, earlier onset diagnosis, and have ovarian/breast cancer within the family (Cunningham 2014). The variant was also identified in dbSNP (ID: rs80358815) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; HGMD, Clinvitae database (as pathogenic), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports; in addition to being classified as pathogenic by BIC and Ambry Genetics, likely pathogenic by Counsyl, and classification not provided by Invitae), GeneInsight COGR database (2X, classified as pathogenic and likely pathogenic by 2 clinical laboratories), the BIC database (14X with pathogenic clinical importance), and UMD (1X as a causal variant). The variant was also identified by our laboratory in 1 individual(s) with ovarian cancer.The p.Ser1955X variant leads to a premature stop codon at position 1955, 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 meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077364 SCV000733275 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000221022 SCV000778692 pathogenic not provided 2017-12-13 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735576 SCV000863714 pathogenic Breast and/or ovarian cancer 2014-10-13 no assertion criteria provided clinical testing

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