ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2861dup (p.Ser955fs) (rs886040079)

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Total submissions: 6
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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) RCV000257600 SCV000323528 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 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 RCV000257600 SCV000325480 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657439 SCV000779174 pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA1 is denoted c.2861dupT at the cDNA level and p.Ser955IlefsX16 (S955IfsX16) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGTC[dupT]ATCA. The duplication causes a frameshift which changes a Serine to an Isoleucine at codon 955, and creates a premature stop codon at position 16 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779904 SCV000916806 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2861dupT (p.Ser955IlefsX16) 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.2864C>A, p.Ser955X; c.2868delT, p.Gln957fsX43; c.2901_2902dupTC, p.Pro968fsX33). The variant was absent in 246124 control chromosomes (gnomAD). The variant, c.2861dupT, has been reported in the literature in one family affected with Hereditary Breast and Ovarian Cancer (Azzollini_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 likely pathogenic.
Ambry Genetics RCV001016813 SCV001177811 pathogenic Hereditary cancer-predisposing syndrome 2019-05-10 criteria provided, single submitter clinical testing The c.2861dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 2861, causing a translational frameshift with a predicted alternate stop codon (p.S955Ifs*16). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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.
Invitae RCV000779904 SCV001401115 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser955Ilefs*16) 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 variant has been observed in an individual affected with personal and/or family history of breast and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 266311). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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