Submissions for variant NM_000059.4(BRCA2):c.1060T>C (p.Phe354Leu)

dbSNP: rs1318579197

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001973273	SCV002255732	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-27	criteria provided, single submitter	clinical testing	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. 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 BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 1470462). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 354 of the BRCA2 protein (p.Phe354Leu).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003156934	SCV003849812	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	RCV003156934	SCV003995778	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.F354L variant (also known as c.1060T>C), located in coding exon 9 of the BRCA2 gene, results from a T to C substitution at nucleotide position 1060. The phenylalanine at codon 354 is replaced by leucine, an amino acid with highly 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.
All of Us Research Program, National Institutes of Health	RCV004011016	SCV004838381	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 354 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/248752 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.