Submissions for variant NM_007294.4(BRCA1):c.2171C>T (p.Pro724Leu)

gnomAD frequency: 0.00001  dbSNP: rs751104940

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000705073	SCV000834053	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 724 of the BRCA1 protein (p.Pro724Leu). This variant is present in population databases (rs751104940, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29020732, 30725392). ClinVar contains an entry for this variant (Variation ID: 581291). 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	RCV001183206	SCV001348869	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 724 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 29020732). This variant has been identified in 2/250828 chromosomes 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001183206	SCV003849444	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	RCV001183206	SCV004058400	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.P724L variant (also known as c.2171C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2171. The proline at codon 724 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with ovarian cancer (Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925). 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.