ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.3373C>T (p.Arg1125Ter) (rs139603739)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483712 SCV000570317 uncertain significance not provided 2016-05-12 criteria provided, single submitter clinical testing This variant is denoted POLE c.3373C>T at the cDNA level and p.Arg1125Ter (R1125X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. While some missense variants in POLE have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLE Arg1125Ter to be a variant of uncertain significance with respect to cancer.To date, the majority of publications regarding POLE and colorectal cancer risk are confined to missense variants within the exonuclease domain (Palles 2013, Spier 2015). However, a splice variant and a frameshift variant have been reported. Pachlopnik Schmid et al. (2012) observed a splice variant at the +3 position in intron 34, in the homozygous state, in 11 family members with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) from a large consanguineous family; however, they noted that all heterozygous carriers were asymptomatic and did not have a history of cancer. While Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, no family history was provided and segregation analysis was not completed. As described above, facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) appears to be a rare autosomal recessive condition associated with two loss-of-function variants in POLE (Pachlopnik Schmid 2012). For individuals and family members of reproductive age, assessment of the reproductive risk associated with being a carrier of a loss of function POLE variant may be considered.
Invitae RCV000650885 SCV000772734 uncertain significance Colorectal cancer, susceptibility to, 12 2019-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1125*) in the POLE gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs139603739, ExAC 0.01%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 421197). Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein, while not abolishing its polymerase enzyme activity, are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). Loss-of-function truncating variants, which result in an absent or severely disrupted POLE protein, are therefore unlikely to be associated with disease. Without further clinical and genetic evidence, however, this variant has been classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV000483712 SCV000928145 likely pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001020121 SCV001181558 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-28 criteria provided, single submitter clinical testing Insufficient evidence

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