ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4550T>C (p.Leu1517Pro)

dbSNP: rs1555581980
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509594 SCV000608089 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-11 criteria provided, single submitter clinical testing The p.L1517P variant (also known as c.4550T>C), located in coding exon 13 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4550. The leucine at codon 1517 is replaced by proline, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000538536 SCV000635981 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1517 of the BRCA1 protein (p.Leu1517Pro). 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: 441429). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000509594 SCV001347404 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-06 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 1517 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 30213835). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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