ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5232_5238delinsGTCCAAAGCGAG (p.Asn1745fs) (rs483353071)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523467 SCV000618494 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA1 c.5232_5238delAAACCACins12 at the cDNA level and p.Asn1745SerfsX22 (N1745SfsX22) at the protein level. The surrounding sequence is GAAG[delAAACCAC][ins12]CAAG. The variant causes a frameshift which changes an Asparagine to a Serine at codon 1745, and creates a premature stop codon at position 22 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. Also reported as BRCA1 5232del7ins12 and 5351del7ins12, using alternate nomenclature, this variant has been observed in individuals evaluated for Hereditary Breast and Ovarian Cancer (Judkins 2005, Kluska 2015). We consider BRCA1 c.5232_5238delAAACCACins12 to be pathogenic.
Invitae RCV000539788 SCV000636022 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1745Serfs*22) 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 a personal and/or family history of early-onset breast/ovarian cancer (PMID: 25948282). This variant is also known as c.5232del7ins12 in the literature. ClinVar contains an entry for this variant (Variation ID: 449982). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000539788 SCV001339250 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5232_5238delins12 (c.5232_5238delinsGTCCAAAGCGAG; p.Asn1745SerfsX22) 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 not detected in approximately 21,000 chromosomes in the gnomAD structural variants database. c.5232_5238delins12 has been reported in the literature in at least one individual affected with familial or early-onset Breast and/or Ovarian Cancer (Kluska_2015). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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