ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.1636G>A (p.Gly546Ser)

gnomAD frequency: 0.00007  dbSNP: rs768676143
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413212 SCV000492064 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The G546S variant in the FANCM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G546S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G546S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G546S as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001222225 SCV001394318 uncertain significance Fanconi anemia 2022-10-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 546 of the FANCM protein (p.Gly546Ser). This variant is present in population databases (rs768676143, gnomAD 0.009%). 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: 373472). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 RCV002481278 SCV002786535 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2022-01-18 criteria provided, single submitter clinical testing

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