ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.178G>A (p.Val60Ile) (rs138629441)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563479 SCV000673290 likely benign Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data,In silico models in agreement (benign) ,Other strong data supporting benign classification,Other data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224234 SCV000493642 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224234 SCV000281625 likely benign not provided 2015-08-19 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
GeneDx RCV000115347 SCV000149256 likely benign not specified 2017-10-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000115347 SCV000917336 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: FANCC c.178G>A (p.Val60Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 279000 control chromosomes. This frequency is lower than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00088 vs 0.0018), allowing no conclusion about variant significance. c.178G>A has been reported in the literature in individuals affected with breast, prostate, pancreatic cancers, and head and neck squamous cell carcinoma as well as in healthy controls (Seal_2003, Thompson_2010, Chandrasekharappa_2017, Couch_2005). These report(s) suggest that c.178G>A (legacy name 433G>A) is unlikely to be associated with these type of cancer, but do 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, but multiple authors consider the variant as neutral polymorphism (Savoia_1996; Verhagen_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign 3X; VUS 2X). Based on the evidence outlined above, the variant was classified as Likely Benign.
Invitae RCV000197543 SCV000254258 uncertain significance Fanconi anemia 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 60 of the FANCC protein (p.Val60Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs138629441, ExAC 0.1%). This variant has been reported in individuals affected with breast and pancreatic cancer, as well as unaffected individuals (PMID: 14695169, 23028338, 15695377, 8799375). ClinVar contains an entry for this variant (Variation ID: 127537). 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 isoleucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000709095 SCV000838360 uncertain significance Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing

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