Submissions for variant NM_000059.4(BRCA2):c.1558T>G (p.Phe520Val)

gnomAD frequency: 0.00001  dbSNP: rs80358441

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012153	SCV001172574	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-03	criteria provided, single submitter	clinical testing	The p.F520V variant (also known as c.1558T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1558. The phenylalanine at codon 520 is replaced by valine, an amino acid with highly similar properties. This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264457	SCV001442623	uncertain significance	not specified	2020-10-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1558T>G (p.Phe520Val) 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 allele was found at a frequency of 8.5e-06 in 234680 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1558T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.5503C>T, p.Arg1835X; BIC database). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313921	SCV001504432	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 520 of the BRCA2 protein (p.Phe520Val). This variant is present in population databases (rs80358441, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51143). 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000112935	SCV002030308	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV001012153	SCV003851485	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).
Myriad Genetics, Inc.	RCV000112935	SCV004018656	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001012153	SCV004361228	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 520 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 been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007838). This variant has been identified in 2/234680 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.
All of Us Research Program, National Institutes of Health	RCV000112935	SCV004839071	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 520 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 been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007838). This variant has been identified in 2/234680 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112935	SCV000145888	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112935	SCV004244222	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing