ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1201G>A (p.Gly401Arg) (rs730881722)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160485 SCV000211050 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1201G>A at the cDNA level, p.Gly401Arg (G401R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant, also denoted FANCC c.1456G>A using alternate nomenclature, was observed in one individual with a personal history of pancreatic cancer (1/421) and was absent in control individuals (0/654) without a personal history of pancreatic and/or colon cancer (Couch 2005). FANCC Gly401Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Gly401Arg occurs at a position that is conserved across species and is located in the Hsp70 binding domain (Gordon 2000). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Additionally, multiple splicing models predict the creation of a new cryptic splice acceptor site downstream of the natural splice acceptor site of intron 12, which may lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether FANCC Gly401Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630920 SCV000751894 uncertain significance Fanconi anemia 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 401 of the FANCC protein (p.Gly401Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs730881722, ExAC 0.001%). This variant was reported in an individual affected with pancreatic cancer (PMID: 15695377). This variant is also known as c.1456G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 182484). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.

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