ClinVar Miner

Submissions for variant NM_001113378.1(FANCI):c.3041G>A (p.Cys1014Tyr) (rs140404896)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778450 SCV000914698 likely pathogenic Fanconi anemia, complementation group I 2017-09-06 criteria provided, single submitter clinical testing The FANCI c.3041G>A (p.Cys1014Tyr) missense variant has been reported in three studies in which it is found in a total of six individuals including in three with Fanconi anemia, one in a homozygous state and two in a compound heterozygous state with a second null allele. One of the compound heterozygous individuals was also diagnosed with the VACTERL phenotype. The p.Cys1014Tyr variant was also reported in a heterozygous state in three individuals, one with breast cancer and two with prostate cancer (Ameziane et al. 2012; Mantere et al. 2015; Savage et al. 2016). The p.Cys1014Tyr variant was reported in four of 1365 controls in a heterozygous state and is reported at a frequency of 0.000853 in the European (Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Cys1014Tyr variant is classified as likely pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001239482 SCV001412358 likely pathogenic Fanconi anemia 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1014 of the FANCI protein (p.Cys1014Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs140404896, ExAC 0.05%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 22720145, 24989076, 26590883). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 631744). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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