Submissions for variant NM_020937.4(FANCM):c.5068G>A (p.Val1690Ile)

dbSNP: rs752352756

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322799	SCV001513688	uncertain significance	Fanconi anemia	2023-07-17	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022842). 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 isoleucine 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. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1690 of the FANCM protein (p.Val1690Ile). This variant is present in population databases (no rsID available, gnomAD 0.0008%).
GeneDx	RCV001527777	SCV001738910	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001820015	SCV002065794	uncertain significance	not specified	2021-12-07	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with FANCM-related disorders. This sequence change has been described in the gnomAD database in two heterozygous individual which corresponds to a population frequency of 0.00071%(dbSNP rs752352756). The p.Val1690Ile change affects a poorly conserved amino acid residue located in a domain of the FANCM protein that is not known to be functional. The p.Val1690Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Val1690Ile change remains unknown at this time.