ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.843+5G>A

gnomAD frequency: 0.00006  dbSNP: rs369082921
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200370 SCV000254265 uncertain significance Fanconi anemia 2022-10-29 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the FANCC gene. It does not directly change the encoded amino acid sequence of the FANCC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369082921, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 216291). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 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.
GeneDx RCV000486099 SCV000566528 likely pathogenic not provided 2023-09-18 criteria provided, single submitter clinical testing Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Observed in a patient with breast cancer (Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS7+5G>A; This variant is associated with the following publications: (PMID: 35264596)
Counsyl RCV000666113 SCV000790355 uncertain significance Fanconi anemia complementation group C 2017-03-16 criteria provided, single submitter clinical testing
Mendelics RCV000666113 SCV000838349 uncertain significance Fanconi anemia complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017767 SCV001178903 likely pathogenic Hereditary cancer-predisposing syndrome 2023-07-20 criteria provided, single submitter clinical testing The c.843+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the FANCC gene. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509295 SCV002819809 uncertain significance not specified 2022-12-25 criteria provided, single submitter clinical testing Variant summary: FANCC c.843+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.843+5G>A in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (LP, n=2; VUS, n=3). Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486099 SCV004218695 uncertain significance not provided 2022-09-30 criteria provided, single submitter clinical testing To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000039 (5/129150 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper FANCC mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.

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