ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1754del (p.Lys585fs) (rs80359301)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000463045 SCV000541006 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077262 SCV000145925 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077262 SCV000326602 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077262 SCV000300458 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000212214 SCV000210714 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.1754delA at the cDNA level and p.Lys585ArgfsX29 (K585RfsX29) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAA[A]GAAA. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 585, and creates a premature stop codon at position 29 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.1754delA, previously reported as BRCA2 1982delA using alternate numbering, has been published as a disease causing variant in association with hereditary breast and/or ovarian cancer (Frank 1998, Kauff 2002, Lubinski 2004, Tai 2007). We therefore consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000043873 SCV000916849 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1754delA (p.Lys585ArgfsX29) 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 (eg. c.1763_1766delATAA (p.Asn588fsX25), c.1792dupA(p.Thr598fsX4), c.1813delA (p.Ile605fsX9)). The variant was absent in 245042 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Mandelker_2017, Tung_2016, Susswein_2015, Nanda_2005, Frank_1998). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000043873 SCV000071886 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-26 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the BRCA2 mRNA (c.1754delA), causing a frameshift at codon 585. This creates a premature translational stop signal (p.Lys585Argfs*29) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer (PMID: 12161607, 25476495, 25850536, 26976419). It has also been reported in a male with breast cancer (PMID: 18042939) and in an individual affected with prostate cancer (PMID: 26681312). This variant is also known as 1982delA in the literature. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077262 SCV000296727 pathogenic Breast-ovarian cancer, familial 2 2015-02-17 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043873 SCV000587606 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077262 SCV000109059 pathogenic Breast-ovarian cancer, familial 2 2011-02-14 no assertion criteria provided clinical testing

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