Submissions for variant NM_001113378.2(FANCI):c.2879_2884dup (p.Gln961_Phe962insTrpGln)

gnomAD frequency: 0.00001  dbSNP: rs776851666

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001806727	SCV002050923	likely benign	not specified	2021-12-10	criteria provided, single submitter	clinical testing	Variant summary: FANCI c.2879_2884dupGGCAAT (p.Gln961_Phe962insTrpGln) results in an in-frame insertion that is predicted to insert two amino acids into the encoded protein. The variant allele was found at a frequency of 6e-05 in 251284 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.9-fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in FANCI causing the Fanconi Anemia phenotype (0.00028). However, in the Korean subpopulation the variant was reported with an even higher allele frequency 0.0029 (i.e. 11 / 3818 alleles) that is ~10-fold higher than the estimated MPAF, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2879_2884dupGGCAAT, has been reported in the literature in two East Asian individuals affected with acute myeloid leukemia (Jeong_2019) and breast cancer (Yang_2015), however 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869492	SCV002286146	uncertain significance	Fanconi anemia	2024-01-04	criteria provided, single submitter	clinical testing	This variant, c.2879_2884dup, results in the insertion of 2 amino acid(s) of the FANCI protein (p.Gln961_Phe962insTrpGln), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776851666, gnomAD 0.08%). This variant has been observed in individual(s) with acute myeloid leukemia (PMID: 31470354). ClinVar contains an entry for this variant (Variation ID: 1331383). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Fulgent Genetics, Fulgent Genetics	RCV005005288	SCV005631045	uncertain significance	Fanconi anemia complementation group I	2024-04-23	criteria provided, single submitter	clinical testing