ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.166-2A>G

gnomAD frequency: 0.00001  dbSNP: rs587777945
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001729399 SCV001976934 pathogenic Fanconi anemia complementation group C 2021-10-01 criteria provided, single submitter clinical testing PVS1, PM2, PP3, PP4
Ambry Genetics RCV002399490 SCV002707549 likely pathogenic Hereditary cancer-predisposing syndrome 2022-02-01 criteria provided, single submitter clinical testing The c.166-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the FANCC gene. This variant has been identified as homozygous in a carrier with hematological abnormalities (Marinakis NM et al. Am J Med Genet A, 2021 08;185:2561-2571).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; however, direct evidence is insufficient at this time (Ambry internal data). 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.
PreventionGenetics, part of Exact Sciences RCV003407527 SCV004108750 pathogenic FANCC-related condition 2022-12-14 criteria provided, single submitter clinical testing The FANCC c.166-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state in an individual with hematological abnormalities (Marinakis et al. 2021. PubMed ID: 34008892. Table S3). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98009800-T-C). Variants that disrupt the consensus splice acceptor site in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic.
Invitae RCV003522928 SCV004286257 likely pathogenic Fanconi anemia 2023-02-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 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). This variant is present in population databases (rs587777945, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with a hematological condition (PMID: 34008892). ClinVar contains an entry for this variant (Variation ID: 135543). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
ITMI RCV000122403 SCV000083954 not provided not specified 2013-09-19 no assertion provided reference population

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