ClinVar Miner

Submissions for variant NM_001113378.2(FANCI):c.824T>C (p.Ile275Thr) (rs142906652)

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
GeneDx RCV000523947 SCV000616715 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing The I275T variant in the FANCI gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I275T variant is observed in 64/66740 (0.095%) alleles from individuals of non-Finnish European background, in the ExAC dataset and no individuals were reported to be homozygous (Lek et al., 2016). The I275T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I275T as a variant of uncertain significance.
Invitae RCV000529696 SCV000626322 uncertain significance Fanconi anemia 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 275 of the FANCI protein (p.Ile275Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs142906652, ExAC 0.1%). This variant has been reported in the literature in an individual with head and neck squamous cell carcinoma (PMID: 28678401) and an individual with breast cancer as well as in unaffected controls (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 449021). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. 5
Illumina Laboratory Services,Illumina RCV001118938 SCV001277260 uncertain significance Fanconi anemia, complementation group I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001118938 SCV001525270 uncertain significance Fanconi anemia, complementation group I 2019-06-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001118938 SCV002011135 uncertain significance Fanconi anemia, complementation group I 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821453 SCV002066147 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCI gene demonstrated a sequence change, c.824T>C, in exon 10 that results in an amino acid change, p.Ile275Thr. This sequence change has been described in the gnomAD database with a frequency of 0.11% in the European sub-population (dbSNP rs142906652). The p.Ile275Thr change has been described in one individual with head and neck squamous cell carcinoma (PMID: 28678401). The p.Ile275Thr change affects a highly conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. In-silico predictions pathogenicity prediction tools (SIFT, PoluPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile275Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile275Thr change remains unknown at this time.

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.