Submissions for variant NM_001113378.2(FANCI):c.2507A>G (p.Asn836Ser)

gnomAD frequency: 0.00006  dbSNP: rs933284199

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463193	SCV000547836	uncertain significance	Fanconi anemia	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 836 of the FANCI protein (p.Asn836Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FANCI-related conditions. ClinVar contains an entry for this variant (Variation ID: 408253). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV001121010	SCV001279543	uncertain significance	Fanconi anemia complementation group I	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237865	SCV002011146	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821273	SCV002064729	uncertain significance	not specified	2021-04-16	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with FANCI-related disorders and has been described in the gnomAD database with a low population frequency of 0.0068% (dbSNP rs933284199). The p.Asn836Ser change affects a poorly conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. The p.Asn836Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the FANCI gene, however functional studies have not been performed to prove this conclusively. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn836Ser change remains unknown at this time.
Sema4, Sema4	RCV000463193	SCV002529824	uncertain significance	Fanconi anemia	2022-01-06	criteria provided, single submitter	curation