ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1016del (p.Lys339fs)

dbSNP: rs80357569
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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) RCV000030967 SCV000299521 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Michigan Medical Genetics Laboratories, University of Michigan RCV000030967 SCV000195887 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000222143 SCV000278698 pathogenic Hereditary cancer-predisposing syndrome 2022-02-14 criteria provided, single submitter clinical testing The c.1016delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1016, causing a translational frameshift with a predicted alternate stop codon (p.K339Rfs*2). This alteration, also described as 1135delA and 1129delA, has been detected in multiple, ethnically diverse breast and/or ovarian cancer patients/ families (Hogervorst FB et al. Nat. Genet. 1995 Jun;10(2):208-12; Janatová M et al. Neoplasma 2003; 50(4):246-50; Pohlreich P et al. Med Princ Pract; 2003;12(1):23-9; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488; Concolino P et al. Int J Mol Sci. 2019 Jul;20:; Laitman Y et al. Hum Mutat. 2019 11;40:e1-e23; Shao D et al. Cancer Sci. 2020 Feb;111:647-657). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030967 SCV000324929 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507496 SCV000600235 pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing
GeneDx RCV000507496 SCV000778879 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.1016delA at the cDNA level and p.Lys339ArgfsX2 (K339RfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAAAA[delA]GGTA. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 339, and creates a premature stop codon at position 2 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. BRCA1 c.1016delA, previously published as 1129delA and 1135delA using alternate nomenclature, has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (Hagervorst 1995, Polreich 2003, Kwong 2009, Fang 2014, Rebbeck 2016). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496871 SCV001364036 pathogenic Hereditary breast ovarian cancer syndrome 2019-11-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1016delA (p.Lys339ArgfsX2) 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. The variant was absent in 251174 control chromosomes (gnomAD). c.1016delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, Laitman_2019). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters including one expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000496871 SCV001586457 pathogenic Hereditary breast ovarian cancer syndrome 2023-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys339Argfs*2) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 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/or ovarian cancer (PMID: 7663517, 15024741, 16287141, 16683254, 22970155, 27157322, 27836010). This variant is also known as 1129delA and 1135delA. ClinVar contains an entry for this variant (Variation ID: 37386). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000222143 SCV001735006 pathogenic Hereditary cancer-predisposing syndrome 2020-12-23 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 7663517, 9150151, 10874312, 11463009, 16168118, 19353265, 22970155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics RCV000030967 SCV004216915 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-09-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030967 SCV000053558 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2009-05-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030967 SCV000143983 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000496871 SCV000587093 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000030967 SCV000733663 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
CZECANCA consortium RCV001270960 SCV001451764 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357938 SCV001553548 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000507496 SCV001905740 pathogenic not provided no assertion criteria provided clinical testing

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