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

gnomAD frequency: 0.00071  dbSNP: rs142906652

Total submissions: 9

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	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 275 of the FANCI protein (p.Ile275Thr). This variant is present in population databases (rs142906652, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with head and neck squamous cell carcinoma or breast cancer (PMID: 28678401, 30303537). ClinVar contains an entry for this variant (Variation ID: 449021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCI protein function. 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.
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	RCV000523947	SCV002011135	uncertain significance	not provided	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.
Sema4, Sema4	RCV000529696	SCV002532083	uncertain significance	Fanconi anemia	2022-03-07	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001118938	SCV002775731	uncertain significance	Fanconi anemia complementation group I	2022-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821453	SCV004241058	likely benign	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: FANCI c.824T>C (p.Ile275Thr) results in a non-conservative amino acid change located in the FANCI solenoid 1 domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251470 control chromosomes. The observed variant frequency is approximately 1.98 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCI causing Fanconi Anemia phenotype (0.00028), strongly suggesting that the variant is benign. c.824T>C has been reported in the literature in individuals affected with various cancer phenotypes including colorectal, head and neck and breast cancer (Poliani_2022, Chandrasekharappa_2018, Girard_2019). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28678401, 30303537, 36356413). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.