Submissions for variant NM_000059.4(BRCA2):c.4790C>T (p.Ser1597Phe)

dbSNP: rs876660146

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023050	SCV001184866	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-21	criteria provided, single submitter	clinical testing	The p.S1597F variant (also known as c.4790C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4790. The serine at codon 1597 is replaced by phenylalanine, an amino acid with highly dissimilar 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.
Color Diagnostics, LLC DBA Color Health	RCV001023050	SCV001356564	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1597 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862247	SCV002152258	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-04-08	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. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 825172). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 1597 of the BRCA2 protein (p.Ser1597Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001023050	SCV003852098	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).
All of Us Research Program, National Institutes of Health	RCV004803377	SCV005424452	uncertain significance	BRCA2-related cancer predisposition	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1597 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. 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 not been reported in individuals affected with hereditary cancer in the literature. 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.