ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.233C>A (p.Pro78His)

gnomAD frequency: 0.00002  dbSNP: rs138722298
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481574 SCV000566398 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing This variant is denoted FANCC c.233C>A at the cDNA level, p.Pro78His (P78H) at the protein level, and results in the change of a Proline to a Histidine (CCT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Pro78His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Pro78His occurs at a position that is conserved across species and is located in the region of interaction with RED (Gordon & Buchwald 2000). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether FANCC Pro78His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000531726 SCV000626242 uncertain significance Fanconi anemia 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the FANCC protein (p.Pro78His). This variant is present in population databases (rs138722298, gnomAD 0.007%). 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: 418955). 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 expected to disrupt FANCC protein function with a positive 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 RCV002446920 SCV002733020 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-17 criteria provided, single submitter clinical testing The p.P78H variant (also known as c.233C>A), located in coding exon 2 of the FANCC gene, results from a C to A substitution at nucleotide position 233. The proline at codon 78 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 RCV002469168 SCV002765925 uncertain significance not specified 2022-11-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001276595 SCV002814860 uncertain significance Fanconi anemia complementation group C 2022-05-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481574 SCV004218671 uncertain significance not provided 2022-09-28 criteria provided, single submitter clinical testing The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000008 (2/251164 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc. RCV001276595 SCV001463022 uncertain significance Fanconi anemia complementation group C 2018-07-28 no assertion criteria provided clinical testing

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