ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.1576C>G (p.Leu526Val) (rs144215747)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763929 SCV000894873 uncertain significance SPERMATOGENIC FAILURE 28; PREMATURE OVARIAN FAILURE 15 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000484209 SCV000573452 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing The L526V variant in the FANCM gene has been reported previously in the heterozygous state in two individuals of Spanish descent with a history of breast cancer (Garcia et al., 2009). The L526V variant has not been reported previously in association with Fanconi anemia. Although not present in the homozygous state, the L526V variant is observed in 24/11228 (0.21%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The L526V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret L526V as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000383479 SCV000386748 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000383479 SCV000547794 uncertain significance Fanconi anemia 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 526 of the FANCM protein (p.Leu526Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs144215747, ExAC 0.2%). This variant has been reported in the literature in two individuals affected with breast cancer (PMID: 19737859). ClinVar contains an entry for this variant (Variation ID: 313199). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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