ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.521+1G>A (rs145394391)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230742 SCV000283594 likely pathogenic Fanconi anemia 2020-06-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the FANCC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with prostate cancer (PMID: 29439820). ClinVar contains an entry for this variant (Variation ID: 237074). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780230 SCV000917332 likely pathogenic Fanconi anemia, complementation group C 2020-10-17 criteria provided, single submitter clinical testing Variant summary: FANCC c.521+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251136 control chromosomes. c.521+1G>A has been reported in the literature in at-least one individual affected with Prostate cancer (example, Antonarakis_2018). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one locus specific database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. The locus specific database for FANCC reports a classification of Pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000780230 SCV001163625 pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Ambry Genetics RCV001023734 SCV001185649 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-04 criteria provided, single submitter clinical testing The c.521+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the FANCC gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
Leiden Open Variation Database RCV000780230 SCV001365300 pathogenic Fanconi anemia, complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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