Submissions for variant NM_007294.4(BRCA1):c.2093C>T (p.Pro698Leu)

dbSNP: rs1555590478

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573001	SCV000668417	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	clinical testing	The p.P698L variant (also known as c.2093C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2093. The proline at codon 698 is replaced by leucine, an amino acid with similar properties. 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.
Invitae	RCV000820698	SCV000961421	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-12	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 698 of the BRCA1 protein (p.Pro698Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ependymoma and/or high-risk of breast cancer and/or ovarian cancer (PMID: 22476429, 26580448). ClinVar contains an entry for this variant (Variation ID: 482905). 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	RCV000573001	SCV001359378	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 698 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and ovarian cancer family (PMID: 22476429) and in an individual affected with pediatric ependymoma (PMID: 26580448). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527065	SCV001737905	uncertain significance	not specified	2021-12-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2093C>T (p.Pro698Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251184 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2093C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and with ependymoma (e.g. Lu_2012, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000573001	SCV003849506	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).