Submissions for variant NM_001018115.3(FANCD2):c.2803A>C (p.Ile935Leu)

gnomAD frequency: 0.00029  dbSNP: rs61751578

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459317	SCV000547223	uncertain significance	Fanconi anemia	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 935 of the FANCD2 protein (p.Ile935Leu). This variant is present in population databases (rs61751578, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 407784). 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 FANCD2 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.
CeGaT Center for Human Genetics Tuebingen	RCV000512981	SCV000609096	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764455	SCV000895517	uncertain significance	Fanconi anemia complementation group D2	2022-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764455	SCV001306225	uncertain significance	Fanconi anemia complementation group D2	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	RCV000764455	SCV001482812	uncertain significance	Fanconi anemia complementation group D2	2020-12-01	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	RCV000512981	SCV002011322	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821251	SCV002066662	uncertain significance	not specified	2021-10-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCD2 gene demonstrated a sequence change, c.2803A>C, in exon 29 that results in an amino acid change, p.Ile935Leu. This sequence change does not appear to have been previously described in individuals with FANCD2-related disorders and has been described in the gnomAD database with a frequency of 0.046% in the European sub-population (dbSNP rs61751578). The p.Ile935Leu change affects a moderately conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. The p.Ile935Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile935Leu change remains unknown at this time.