ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5463_5464insT (p.His1822fs)

dbSNP: rs1057518636
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Total submissions: 4
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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) RCV000661034 SCV000783279 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413916 SCV000492463 pathogenic Breast neoplasm criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV000775092 SCV000909197 pathogenic Hereditary cancer-predisposing syndrome 2023-01-10 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 22 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two unrelated individuals affected with breast or ovarian cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 24884479, 27741520, 28947987, 29907814). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV001390964 SCV001592873 pathogenic Hereditary breast ovarian cancer syndrome 2020-02-17 criteria provided, single submitter clinical testing A different truncation (p.Tyr1853*) that lies downstream of this variant has been determined to be pathogenic (PMID: 21922593, 10811118, 11739404, 12400015, 7894493, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect on BRCA1 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24884479, 28947987). This variant is also known as 5582insT in the literature. ClinVar contains an entry for this variant (Variation ID: 373823). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRCA1 gene (p.His1822Serfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acids of the BRCA1 protein.

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