ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5542del (p.Ser1848fs) (rs80359519)

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Total submissions: 11
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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) RCV000077353 SCV000300887 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044678 SCV000072691 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1848Valfs*15) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359519, ExAC 0.009%). This variant has been reported in an individual with breast cancer (PMID: 25371446). This variant is also known as 5770delA in the literature. ClinVar contains an entry for this variant (Variation ID: 51878). 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 RCV000130725 SCV000185613 pathogenic Hereditary cancer-predisposing syndrome 2017-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000218498 SCV000279284 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.5542delA at the cDNA level and p.Ser1848ValfsX15 (S1848VfsX15) at the protein level. The normal sequence, with the base that is deleted in braces, is AGCC[A]GTGG. The deletion causes a frameshift, which changes a Serine to a Valine at codon 1848, and creates a premature stop codon at position 15 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.5542delA, previously reported as 5770delA, has been reported in association with familial breast cancer (Torres-Mejia 2015). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218498 SCV000296710 pathogenic not provided 2015-03-09 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077353 SCV000327224 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077353 SCV000677684 likely pathogenic Breast-ovarian cancer, familial 2 2015-03-11 criteria provided, single submitter clinical testing
Color RCV000130725 SCV000683709 pathogenic Hereditary cancer-predisposing syndrome 2016-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044678 SCV000694879 pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5542delA (p.Ser1848ValfsX15) 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. The variant allele was found at a frequency of 4e-06 in 248448 control chromosomes. c.5542delA has been reported in the literature in multiple individuals of Mexican/Hispanic/Latino/Carribean ancestry affected with Hereditary Breast and Ovarian Cancer (example Torres-Mejia_2015, Tung_2014, Rebbeck_2018, Fernandez-Lopez_2019). 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. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077353 SCV000109150 pathogenic Breast-ovarian cancer, familial 2 2012-10-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077353 SCV000146631 pathogenic Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing

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