ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3477_3480del (p.Ile1159fs) (rs80357781)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215402 SCV000275708 pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 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) RCV000077550 SCV000144772 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077550 SCV000325662 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) RCV000077550 SCV000299950 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 RCV000235430 SCV000293467 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in BRCA1 is denoted c.3477_3480delAAAG at the cDNA level and p.Ile1159MetfsX50 (I1159MfsX50) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAT[delAAAG]GAAG. The deletion causes a frameshift, which changes an Isoleucine to a Methionine at codon 1159, and creates a premature stop codon at position 50 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.3477_3480delAAAG, also published as 3596delAAAG and 3596del4 using alternate nomenclature, has been observed in association with breast and ovarian cancer (Montagna 1996, Stuppia 2003, Cortesi 2000, Saxena 2006). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000048209 SCV000916712 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3477_3480delAAAG (p.Ile1159MetfsX50) 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. The variant was observed with an allele frequency of 4.1e-06 in 246080 control chromosomes (gnomAD). The variant, c.3477_3480delAAAG, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000048209 SCV000076222 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 10 of the BRCA1 mRNA (c.3477_3480delAAAG), causing a frameshift at codon 1159. This creates a premature translational stop signal (p.Ile1159Metfs*50) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in individuals affected with breast and ovarian cancer (PMID: 8968102, 10612800, 12872265, 17018160, 26187060). This variant is also known as 3596delAAAG and 3596del4 in the literature. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000048209 SCV000839255 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077550 SCV000109351 pathogenic Breast-ovarian cancer, familial 1 2013-01-17 no assertion criteria provided clinical testing

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