Submissions for variant NM_000136.3(FANCC):c.1561G>A (p.Glu521Lys)

gnomAD frequency: 0.00004  dbSNP: rs752855423

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215546	SCV000279409	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with male breast cancer (Rizzolo et al., 2019); This variant is associated with the following publications: (PMID: 12750283, 24163242, 29599312, 30613976, Gordon2000[Book], 15277238)
Invitae	RCV000706885	SCV000835959	uncertain significance	Fanconi anemia	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 521 of the FANCC protein (p.Glu521Lys). This variant is present in population databases (rs752855423, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976). ClinVar contains an entry for this variant (Variation ID: 234512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV001012190	SCV001172613	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	The p.E521K variant (also known as c.1561G>A), located in coding exon 14 of the FANCC gene, results from a G to A substitution at nucleotide position 1561. The glutamic acid at codon 521 is replaced by lysine, an amino acid with similar properties. This alteration was identified in an male diagnosed with breast cancer (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This amino acid position is highly 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.
Natera, Inc.	RCV000706885	SCV002081134	uncertain significance	Fanconi anemia	2018-08-12	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150986	SCV003839507	uncertain significance	not specified	2022-11-29	no assertion criteria provided	clinical testing	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.1561G>A, in exon 15 results in an amino acid change, p.Glu521Lys. This sequence change has been previously described in an individual with male breast cancer (PMID: 30613976). This sequence change has been described in the gnomAD database with a global population frequency of 0.002% (dbSNP rs752855423). The p.Glu521Lys change affects a highly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu521Lys substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu521Lys change remains unknown at this time.