ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5035del (p.Thr1679fs) (rs80359477)

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Total submissions: 13
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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) RCV000031520 SCV000300818 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000164040 SCV000214646 pathogenic Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing The c.5035delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 5035, causing a translational frameshift with a predicted alternate stop codon (p.T1679Lfs*3). This mutation, referred to as 5263delA, has previously been detected in a woman diagnosed with breast cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210136 SCV000266041 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031520 SCV000327120 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000478488 SCV000569474 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.5035delA at the cDNA level and p.Thr1679LeufsX3 (T1679LfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is GAAAA[A]CTTC. The deletion causes a frameshift which changes a Threonine to a Leucine at codon 1679, and creates a premature stop codon at position 3 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.5035delA, previously reported as BRCA2 5263delA, has been observed in at least one individual with early-onset breast cancer (Foley 2015). We consider this variant to be pathogenic.
Counsyl RCV000031520 SCV000677681 likely pathogenic Breast-ovarian cancer, familial 2 2017-02-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478488 SCV000887835 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164040 SCV000905012 pathogenic Hereditary cancer-predisposing syndrome 2018-04-06 criteria provided, single submitter clinical testing
Invitae RCV000817624 SCV000958193 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1679Leufs*3) 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 observed in individuals with a personal and/or family history of breast and/or ovarian cancers (PMID: 26023681, 26845104, 29446198). This variant is also known as 5263delA in the literature. ClinVar contains an entry for this variant (Variation ID: 37939). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000855 SCV001157929 pathogenic not specified 2018-10-03 criteria provided, single submitter clinical testing The BRCA2 c.5035delA; p.Thr1679fs variant (rs80359477), also known as 5263delA, is reported in the literature in at least one individual affected with breast cancer (Foley 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37939), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Thr1679fs variant is considered to be pathogenic. References: Foley SB et al. Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. EBioMedicine. 2015 Jan;2(1):74-81.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000817624 SCV001360689 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5035delA (p.Thr1679LeufsX3) 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 30916 control chromosomes (gnomAD). c.5035delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Foley_2015, Llort_2002, Rebbeck_2018). 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. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031520 SCV000054125 pathogenic Breast-ovarian cancer, familial 2 2011-01-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031520 SCV000146523 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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