ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.34G>A (p.Asp12Asn)

gnomAD frequency: 0.00002  dbSNP: rs1355767159
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001557430 SCV000772727 uncertain significance not provided 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 12 of the POLE protein (p.Asp12Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 540767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx RCV001557430 SCV001779189 uncertain significance not provided 2019-08-28 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002477449 SCV002777821 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2022-03-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV003162988 SCV003890310 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-25 criteria provided, single submitter clinical testing The c.34G>A (p.D12N) alteration is located in exon 1 (coding exon 1) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 34, causing the aspartic acid (D) at amino acid position 12 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004533405 SCV004120267 uncertain significance POLE-related disorder 2023-07-19 criteria provided, single submitter clinical testing The POLE c.34G>A variant is predicted to result in the amino acid substitution p.Asp12Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133263868-C-T). In ClinVar, this variant is currently listed as 'uncertain significance' by several outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/540767/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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