ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2940del (p.Pro981fs) (rs80357876)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000236676 SCV000885075 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The BRCA1 c.2940delA; p.Pro981fs variant (rs80357876), is reported in the literature in an individual with ovarian cancer (Song 2014), and reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 91603). This variant is absent from the 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, this variant is considered to be pathogenic. REFERENCES Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9.
Ambry Genetics RCV000130182 SCV000185019 pathogenic Hereditary cancer-predisposing syndrome 2016-12-27 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)
Breast Cancer Information Core (BIC) (BRCA1) RCV000077120 SCV000144590 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130182 SCV000903721 pathogenic Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077120 SCV000325502 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077120 SCV000299860 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000236676 SCV000292897 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.2940delA at the cDNA level and p.Pro981HisfsX19 (P981HfsX19) at the protein level. The normal sequence, with the base that is deleted in brackets, is GTAT[delA]CCAC. The deletion causes a frameshift, which changes a Proline to a Histidine at codon 981, and creates a premature stop codon at position 19 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. BRCA1 c.2940delA, also reported as 3059delA using alternate nomenclature, has been reported in at least two individuals with ovarian cancer (Pennington 2014, Song 2014). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000206597 SCV000698990 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-02 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2940delA (p.Pro981Hisfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3764dupA/p.Asn1255fs). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous HBOC patients and is absent in 124124 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000206597 SCV000261453 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro981Hisfs*19) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in an individual with epithelial ovarian cancer (PMID: 24728189). ClinVar contains an entry for this variant (Variation ID: 91603). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077120 SCV000267704 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236676 SCV000600308 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077120 SCV000108917 pathogenic Breast-ovarian cancer, familial 1 2010-12-21 no assertion criteria provided clinical testing

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