ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.565C>G (p.Pro189Ala)

gnomAD frequency: 0.00002  dbSNP: rs377620735
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200314 SCV000254262 uncertain significance Fanconi anemia 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 189 of the FANCC protein (p.Pro189Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. 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: "Benign"; 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271459 SCV002556094 uncertain significance not specified 2022-06-23 criteria provided, single submitter clinical testing Variant summary: FANCC c.565C>G (p.Pro189Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.565C>G has been reported in the literature in an individual diagnosed with Ependymoma, and the authors classified the variant as VUS (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002345716 SCV002652373 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-25 criteria provided, single submitter clinical testing The p.P189A variant (also known as c.565C>G), located in coding exon 6 of the FANCC gene, results from a C to G substitution at nucleotide position 565. The proline at codon 189 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with an ependymoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics RCV001276454 SCV002788090 uncertain significance Fanconi anemia complementation group C 2022-03-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV001276454 SCV001462825 uncertain significance Fanconi anemia complementation group C 2020-09-16 no assertion criteria provided clinical testing

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