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

Total submissions: 6

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.