ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.251-2A>C

dbSNP: rs1057517219
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410988 SCV000486932 likely pathogenic Fanconi anemia complementation group C 2016-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002436231 SCV002745156 likely pathogenic Hereditary cancer-predisposing syndrome 2021-10-06 criteria provided, single submitter clinical testing The c.251-2A>C intronic variant results from an A to C substitution two nucleotides before coding exon 3 in the FANCC gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003522962 SCV004269215 pathogenic Fanconi anemia 2022-11-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371370). Disruption of this splice site has been observed in individual(s) with clinical features of Fanconi anemia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the FANCC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555).

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