ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6482_6485ACAA[1] (p.Lys2162fs) (rs80359598)

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Total submissions: 17
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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) RCV000031630 SCV000282428 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 RCV000044967 SCV000072980 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys2162Asnfs*5) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs770263702, ExAC 0.009%). This variant has been reported in several individuals affected with breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 23479189, 19949876, 25896959, 24156927, 26681312, 24145998, 26026974, 20736950, 26360800, 25586199). This variant is also known as 6710delACAA or 6714delACAA in the literature. ClinVar contains an entry for this variant (Variation ID: 38048). 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 RCV000131034 SCV000185964 pathogenic Hereditary cancer-predisposing syndrome 2018-10-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000212249 SCV000210782 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.6486_6489delACAA at the cDNA level and p.Lys2162AsnfsX5 at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAA[delACAA]CAGT. The deletion causes a frameshift, changing a Lysine to an Asparagine at codon 2162, and creating a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.6486_6489delACAA, also reported as 6714_6717delACAA, 6710delACAA, or 6714del4, has been observed in association with hereditary breast and ovarian cancer syndrome (Bergthorsson 2001, Edwards 2003, Thomassen 2008, de Juan Jimenez 2013) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212249 SCV000296740 pathogenic not provided 2019-06-23 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031630 SCV000327441 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000031630 SCV000577964 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044967 SCV000586968 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031630 SCV000605648 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Counsyl RCV000031630 SCV000677693 pathogenic Breast-ovarian cancer, familial 2 2015-05-21 criteria provided, single submitter clinical testing
Color RCV000131034 SCV000683787 pathogenic Hereditary cancer-predisposing syndrome 2016-12-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044967 SCV000694978 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6486_6489delACAA (p.Lys2162Asnfs) variant (alternatively also known as 6714del4 and 6710delACAA) results in deletion of 4 nucleotides from exon 11 of the BRCA2 mRNA, causing a frameshift that creates a premature stop codon. This is predicted to cause a truncated or absent (due to nonsense mediated decay) BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.6591_6592delTG (p.Glu2198fs), c.7069_7070delCT (p.Leu2357fs), etc.) This variant was found in the large and broad control populations from ExAC in 2/ 118868 chromosomes at a frequency of 0.0000168, which does not exceed maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in numerous HBOC patients, including male breast cancer and prostate cancer patients (Plaschke_2000, Bergthorsson_2001, Thomassen_2008, Tommasi_2008, Alsop_2012, de Juan_2015, Nielsen_ 2017) and also in a female patient with pancreatic cancer (Pishvaian_2017). In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University,Faculty of Medicine Ramathibodi Hospital, Mahidol University RCV000768561 SCV000899224 pathogenic Breast carcinoma 2019-04-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002473 SCV001160421 pathogenic not specified 2019-03-21 criteria provided, single submitter clinical testing The BRCA2 c.6486_6489delACAA; p.Lys2162fs variant (rs80359598) has been reported in individuals affected with breast (de Juan Jimenez 2013), ovarian (Li 2018, Shi 2017), or prostate cancer (Edwards 2003, Edwards 2010). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 38048), and it is observed on only two chromosomes (2/232332 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting four nucleotides, so it 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: de Juan Jimenez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013; 12(4):767-77. Edwards S et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003; 72(1):1-12. Edwards S et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010; 103(6):918-24. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152. Shi T et al. BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer. Int J Cancer. 2017 May 1;140(9):2051-2059.
Sharing Clinical Reports Project (SCRP) RCV000031630 SCV000054237 pathogenic Breast-ovarian cancer, familial 2 2012-06-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031630 SCV000146871 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 RCV000044967 SCV000587852 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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