Submissions for variant NM_000136.3(FANCC):c.1001G>A (p.Arg334Gln)

gnomAD frequency: 0.00001  dbSNP: rs377468919

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115339	SCV000149248	uncertain significance	not provided	2017-06-28	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.1001G>A at the cDNA level, p.Arg334Gln (R334Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Arg334Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. FANCC Arg334Gln occurs at a position that is not conserved and is located within the Hsp70 binding domain (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Arg334Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000630863	SCV000751834	uncertain significance	Fanconi anemia	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 334 of the FANCC protein (p.Arg334Gln). This variant is present in population databases (rs377468919, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 127529). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV001009634	SCV001169726	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The p.R334Q variant (also known as c.1001G>A), located in coding exon 10 of the FANCC gene, results from a G to A substitution at nucleotide position 1001. The arginine at codon 334 is replaced by glutamine, an amino acid with highly similar properties. 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030468	SCV001193576	likely benign	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Natera, Inc.	RCV000630863	SCV002081191	uncertain significance	Fanconi anemia	2019-02-04	no assertion criteria provided	clinical testing