ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.996+1G>T (rs370510954)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254963 SCV000321625 likely pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted FANCC c.996+1G>T or IVS10+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 10 of the FANCC gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on currently available evidence, we consider FANCC c.996+1G>T to be a likely pathogenic variant.
Invitae RCV000458747 SCV000549917 likely pathogenic Fanconi anemia 2019-12-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the FANCC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs370510954, ExAC 0.009%). This variant has been observed in an individual affected with medulloblastoma (PMID: 29753700). ClinVar contains an entry for this variant (Variation ID: 265137). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000574838 SCV000673335 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-28 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Integrated Genetics/Laboratory Corporation of America RCV000412116 SCV000695440 likely pathogenic Fanconi anemia, complementation group C 2016-04-29 criteria provided, single submitter clinical testing Variant summary: The c.996+1G>A in a FANCC gene is a splice-site variant that alters a conserved nucleotide. Mutation taster predicts this variant to be disease-causing. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is present in control dataset of ExAC at a low frequency of 0.0000165 (2/121274chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.00177). The variant has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Likely Pathogenic until additional information becomes available.
Counsyl RCV000412116 SCV000485754 likely pathogenic Fanconi anemia, complementation group C 2016-02-08 no assertion criteria provided clinical testing

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