Submissions for variant NM_000059.4(BRCA2):c.4637T>C (p.Phe1546Ser)

dbSNP: rs397507337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132332	SCV000187420	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.F1546S variant (also known as c.4637T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 4637. The phenylalanine at codon 1546 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000132332	SCV000683639	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044392	SCV001208187	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1546 of the BRCA2 protein (p.Phe1546Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37914). 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 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.
GeneDx	RCV002269258	SCV002552570	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; Also known as 4865T>C; This variant is associated with the following publications: (PMID: 9002670, 22193408)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132332	SCV003850673	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).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031495	SCV004171433	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing	The BRCA2 c.4637T>C (p.Phe1546Ser) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with BRCA2-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031495	SCV000054100	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-12-23	no assertion criteria provided	clinical testing