ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2T>A (p.Met1Lys)

dbSNP: rs879254126
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000578827 SCV000653177 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the POLE mRNA. The next in-frame methionine is located at codon 44. This variant is present in population databases (no rsID available, gnomAD 0.008%). Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive FILS syndrome (PMID: 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 473569). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000578827 SCV000680931 uncertain significance not provided 2018-04-02 criteria provided, single submitter clinical testing The c.2T>A variant in the POLE gene alters the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE c.2T>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). While missense variants located within the exonuclease domain of the POLE gene have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), an autosomal dominant condition associated with polyposis and an increased risk for colon cancer (Palles 2013, Spier 2015), there are no data to support that loss-of-function variants, such as this one, confer the same cancer risks. Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, but no information about family history was provided. We therefore consider POLE c.2T>A to be a variant of unknown significance with respect to cancer. A recessive disease associated with POLE has been reported in the literature. In one large consanguineous family, 14 affected relatives with a syndrome called FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) were all found to be homozygous for POLE c.4444+3A>G, a splice variant which results in a small proportion (~10%) of normal POLE transcript (Pachlopnik Schmid 2012). In addition, an unrelated individual with a suspected chromosome instability syndrome was also found to be homozygous for POLE c.4444+3A>G (Thiffault 2015). We cannot assess whether the variant identified in the current patient would cause the same recessive disease. Individuals and family members of reproductive age may choose to consider assessment of potential reproductive risks.
Ambry Genetics RCV002438474 SCV002747933 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.2T>A), located in coding exon 1 of the POLE gene, results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. However, there exists a possible alternate initiation site just 43 residues downstream. This amino acid position is well conserved on limited sequence alignment. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation. However, as neither this specific alteration nor loss-of-function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains unknown.
GenomeConnect - Invitae Patient Insights Network RCV001535559 SCV001749540 not provided Familial colorectal cancer; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 02-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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