ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3771_3772delinsC (p.Glu1257fs) (rs397507218)

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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) RCV000031128 SCV000300015 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
University of Washington Department of Laboratory Medicine, University of Washington RCV000031128 SCV000266031 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000480299 SCV000564737 pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA1 c.3771_3772delGGinsC at the cDNA level and p.Glu1257AspfsX7 (E1257DfsX7) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is CAGA[GG][C]AGAA. The variant causes a frameshift, which changes a Glutamic acid to an Aspartic acid at codon 1257, and creates a premature stop codon at position 7 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.3771_3772delGGinsC, also published as 3890delGGinsC, was observed in a woman with triple negative breast cancer under the age of 45 (Churpek 2015). Based on currently available information, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480299 SCV000605851 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562457 SCV000661065 pathogenic Hereditary cancer-predisposing syndrome 2019-08-03 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV001193140 SCV001361784 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3771_3772delinsC (p.Glu1257AspfsX7) 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. The variant was absent in 251226 control chromosomes. c.3771_3772delinsC has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Churpek_2015, Hirotsu_2015, Shirts_2016). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031128 SCV000053727 pathogenic Breast-ovarian cancer, familial 1 2010-01-19 no assertion criteria provided clinical testing

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