Submissions for variant NM_000136.3(FANCC):c.1634A>G (p.Lys545Arg)

gnomAD frequency: 0.00001  dbSNP: rs571668582

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214884	SCV000279675	uncertain significance	not provided	2015-12-08	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.1634A>G at the cDNA level, p.Lys545Arg (K545R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Lys545Arg was not observed at a significant allele frequency in 1000 Genomes. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. FANCC Lys545Arg occurs at a position that is not conserved and is located in a region responsible for cdc2 binding (Gordon and Buchwald). 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 Lys545Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000543270	SCV000626240	uncertain significance	Fanconi anemia	2022-02-10	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 545 of the FANCC protein (p.Lys545Arg). This variant is present in population databases (rs571668582, gnomAD 0.04%). 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: 234672). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001012385	SCV001172825	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001355318	SCV003833909	uncertain significance	Fanconi anemia complementation group C	2022-11-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355318	SCV001550176	uncertain significance	Fanconi anemia complementation group C		no assertion criteria provided	clinical testing	The FANCC p.Lys545Arg variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs571668582) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 12 of 246178 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 11 of 30776 chromosomes (freq: 0.0004), European in 1 of 111666 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, and Other populations. The p.Lys545 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000543270	SCV002081121	uncertain significance	Fanconi anemia	2020-03-04	no assertion criteria provided	clinical testing