ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2117C>T (p.Pro706Leu)

dbSNP: rs759655692
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773202 SCV000906786 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing
Invitae RCV001212251 SCV001383830 uncertain significance Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with breast cancer (PMID: 33476590). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 706 of the BRCA1 protein (p.Pro706Leu). This variant is present in population databases (rs759655692, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 628627). 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 33476590). 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.
GeneDx RCV001553218 SCV001774044 uncertain significance not provided 2020-08-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
University of Washington Department of Laboratory Medicine, University of Washington RCV000773202 SCV003849488 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Ambry Genetics RCV000773202 SCV003995315 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-26 criteria provided, single submitter clinical testing The p.P706L variant (also known as c.2117C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2117. The proline at codon 706 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Liu PF et al. Clin Chim Acta, 2021 May;516:55-63). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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