ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1493C>T (p.Ala498Val) (rs730881725)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160489 SCV000211054 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1493C>T at the cDNA level, p.Ala498Val (A498V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant was identified in 1/1,441 breast cancer families and was absent among 464 healthy controls (Thompson 2012). FANCC Ala498Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. FANCC Ala498Val occurs at a position that is not conserved across species and is not located in a known functional domain. 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 Ala498Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204351 SCV000260179 uncertain significance Fanconi anemia 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 498 of the FANCC protein (p.Ala498Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs730881725, ExAC 0.002%). This variant has been reported in an individual with family history of breast cancer (PMID: 23028338). ClinVar contains an entry for this variant (Variation ID: 182488). 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: "Deleterious"; 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.
Ambry Genetics RCV001011857 SCV001172231 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-05 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001167958 SCV001330509 uncertain significance Fanconi anemia, complementation group C 2017-05-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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