ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1512dup (p.Lys505Ter) (rs398122636)

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Total submissions: 7
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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) RCV000077071 SCV000299613 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077071 SCV000325091 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000532876 SCV000635800 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys505*) in the BRCA1 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 particular variant has not been published in the literature, but different changes (c.1511dupG, c.1513A>T) giving rise to the same protein effect (p.Lys505*) have been reported in individuals affected with breast cancer (PMID: 22382806, 12453858). ClinVar contains an entry for this variant (Variation ID: 91554). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657813 SCV000779568 pathogenic not provided 2016-03-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1512dupT at the cDNA level and p.Lys505Ter (K505X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This specific variant has been reported in at least one individual with serous ovarian cancer (Song 2014). Additionally, similar variants resulting in the same protein change, Lys505Ter, have been reported in association with hereditary breast and ovarian cancer (Palmieri 2002, Palomba 2005, Jang 2012, Kim 2012). Therefore, this variant is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000532876 SCV000918674 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1512dupT (p.Lys505X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1518delG (p.Arg507fsX25), c.1556delA (p.Lys519fsX13), c.1621C>T (Gln541X)). The variant has been reported in an affected individual in the literature (Song 2014). Other variants affecting the same codon and causing an equivalent protein level change as the variant of interest have also been found in HBOC patients (Palomba 2005, Park 2017). This variant is absent in 279850 control chromosomes (in gnomAD and publication(s)). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Ambry Genetics RCV001011975 SCV001172369 pathogenic Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Sharing Clinical Reports Project (SCRP) RCV000077071 SCV000108868 pathogenic Breast-ovarian cancer, familial 1 2010-06-28 no assertion criteria provided clinical testing

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