ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.843+1G>A (rs587779909)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204814 SCV000260307 likely pathogenic Fanconi anemia 2020-10-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with triple-negative breast cancer (PMID: 30630526). ClinVar contains an entry for this variant (Variation ID: 127547). 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 RCV000410480 SCV001478667 likely pathogenic Fanconi anemia, complementation group C 2021-01-01 criteria provided, single submitter clinical testing Variant summary: FANCC c.843+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 251408 control chromosomes (gnomAD and Hu_2018). c.843+1G>A has not been reported in the literature in individuals affected with Fanconi Anemia Group C, but has been reported in at-least one individual with triple negative breast cancer (Yi_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and one variant database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000410480 SCV000485681 likely pathogenic Fanconi anemia, complementation group C 2016-01-27 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000410480 SCV001365324 pathogenic Fanconi anemia, complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc. RCV000410480 SCV001458698 likely pathogenic Fanconi anemia, complementation group C 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356332 SCV001551467 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The FANCC c.843+1G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs587779909) as "With Likely pathogenic allele", in ClinVar (classified as likely pathogenic by Invitae and Counsyl), and in LOVD 3.0 (2x). The variant was identified in control databases in 3 of 277168 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34414 chromosomes (freq: 0.00003), European in 2 of 126684 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The c.843+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing relative to the normal allele. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.