ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5912A>G (p.Asn1971Ser)

dbSNP: rs772127913
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505854 SCV000602076 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001764504 SCV000772785 uncertain significance not provided 2025-01-19 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 1971 of the POLE protein (p.Asn1971Ser). This variant is present in population databases (rs772127913, gnomAD 0.02%). This missense change has been observed in individual(s) with FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) syndrome (PMID: 30049826). ClinVar contains an entry for this variant (Variation ID: 439278). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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.
Centre for Translational Omics - GOSgene, University College London RCV000659250 SCV000778566 likely pathogenic Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-03-16 criteria provided, single submitter clinical testing
GeneDx RCV001764504 SCV001989269 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the compound heterozygous state with POLE p.Glu1956Val in an individual reportedly presenting with a FILS-like (facial dysmorphism, immunodeficiency, livedo, and short stature) phenotype (Mestek-Boukhibar 2018). While POLE c.4444+3A>G, a leaky splice variant, has been reported as homozygous in individuals with FILS (Pachlopnik Schmid 2012, Thiffault 2015), it is not clear whether biallelic POLE missense variants result in a similar phenotype.; This variant is associated with the following publications: (PMID: 30049826)
Ambry Genetics RCV004943936 SCV005481508 likely benign Hereditary cancer-predisposing syndrome 2024-08-29 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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