ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.981_982del (p.Thr327_Cys328insTer) (rs80357772)

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Total submissions: 12
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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) RCV000077636 SCV000282351 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000049211 SCV000077224 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys328*) 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 reported in an individual with colon cancer (PMID: 26026974), individuals with breast cancer (PMID: 8531968, 24578176, 24961674, 27257965), and families affected with hereditary breast and ovarian cancer (PMID: 22970155, 23479189, 26187060, 26848529). This variant is also known as 1100delAT and 981delAT in the literature. ClinVar contains an entry for this variant (Variation ID: 55772). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162892 SCV000213379 pathogenic Hereditary cancer-predisposing syndrome 2017-03-30 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)
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240695 SCV000265855 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077636 SCV000326480 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000162892 SCV000683379 pathogenic Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing
GeneDx RCV000657804 SCV000779559 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.981_982delAT at the cDNA level and p.Cys328Ter (C328X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as BRCA1 1100delAT using alternate nomenclature, has been observed in individuals with familial or early-onset breast and/or ovarian cancer (FitzGerald 1996, Thirthagiri 2008, Kwong 2012, Azzollini 2016, Sun 2017, Wu 2017). We consider this variant to be pathogenic.
3DMed Clinical Laboratory Inc RCV000240695 SCV000803954 pathogenic Neoplasm of the breast 2017-05-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049211 SCV000918691 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.981_982delAT (p.Cys328X) 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 (e.g. c.1016dupA (p.Val340fsX6), c.1054G>T (p.Glu352X), c.1091_1092delCT (p.Pro364fsX4)). The variant was absent in 277146 control chromosomes. c.981_982delAT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer (see e.g. Aretini 2003, Wu 2017). These data indicate that the variant is very likely to be associated with disease. A publication also reported experimental evidence that primary (non neoplastic) mammary epithelial cells (obtained from tumour-free women) carrying the variant, were defective in stalled replication fork repair (i.e. suppression of replication stress) that contributes to tumorigenesis in BRCA1-deficient mammary tissue (Pathania 2014). Five 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.
Sharing Clinical Reports Project (SCRP) RCV000077636 SCV000109439 pathogenic Breast-ovarian cancer, familial 1 2013-01-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077636 SCV000143972 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000049211 SCV000587091 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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