Submissions for variant NM_000136.3(FANCC):c.990C>G (p.Ser330Arg)

gnomAD frequency: 0.00003  dbSNP: rs374915316

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481385	SCV000571782	uncertain significance	not provided	2023-04-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Gordon2000[Book])
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630962	SCV000751938	uncertain significance	Fanconi anemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 330 of the FANCC protein (p.Ser330Arg). This variant is present in population databases (rs374915316, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 36315513). ClinVar contains an entry for this variant (Variation ID: 422336). 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 FANCC protein function with a negative predictive value of 80%. 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	RCV001019882	SCV001181294	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.S330R variant (also known as c.990C>G), located in coding exon 9 of the FANCC gene, results from a C to G substitution at nucleotide position 990. The serine at codon 330 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with breast cancer (McDonald JT et al. PLoS One, 2022 Oct;17:e0273835). This amino acid position is poorly 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000630962	SCV002526012	uncertain significance	Fanconi anemia	2022-03-22	criteria provided, single submitter	clinical testing	The FANCC c.990C>G (p.Ser330Arg) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/9-97887374-G-T?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4.
Fulgent Genetics, Fulgent Genetics	RCV002475940	SCV002790794	uncertain significance	Fanconi anemia complementation group C	2022-02-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000630962	SCV002081194	uncertain significance	Fanconi anemia	2018-11-13	no assertion criteria provided	clinical testing