ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4674A>G (p.Leu1558=)

gnomAD frequency: 0.00001  dbSNP: rs996042036
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569235 SCV000661078 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-05 criteria provided, single submitter clinical testing The c.4674A>G variant (also known as p.L1558L), located in coding exon 13 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4674. This nucleotide substitution does not change the leucine at codon 1558. This alteration breast cancer (Kataki A et al. Clin. Genet. 2005 Apr;67:322-9). It was also reported in a cohort of Czech patients referred for genetic testing (Machackova E et al. Klin Onkol, 2019;32:51-71), and in cohort of early-onset cases of breast cancer (Shen M et al. Transl Cancer Res. 2019 Apr;8(2):483-490). Of note, this alteration is also known as 4793A>G in some of the published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. One study reporting RNA data shows that this alteration leads to use of a cryptic splice donor site 11 nucleotides upstream of the native site; however the splice defect was considered incomplete (Baert A et al. Hum. Mutat., 2018 04;39:515-526). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000569235 SCV000906742 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001302590 SCV001491804 likely pathogenic Hereditary breast ovarian cancer syndrome 2024-08-12 criteria provided, single submitter clinical testing This sequence change affects codon 1558 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 479230). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 29280214; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV004569094 SCV005058223 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-22 criteria provided, single submitter clinical testing

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