ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.4444+3A>G (rs398122515)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000796781 SCV000936309 likely pathogenic Colorectal cancer, susceptibility to, 12 2019-03-20 criteria provided, single submitter clinical testing This sequence change falls in intron 34 of the POLE gene. It does not directly change the encoded amino acid sequence of the POLE protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome) in two families (PMID: 23230001, 25948378). In these families, heterozygote carriers of this variant were clinically unaffected. ClinVar contains an entry for this variant (Variation ID: 41417). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change leads to altered mRNA splicing and reduced POLE protein expression (PMID: 23230001). In summary, this intronic variant has been observed as homozygous in individuals with FILS syndrome, but has not been observed as a heterozygous variant in individuals with colonic adenomatous polyps or colon cancer. 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 variants, which result in an absent or severely disrupted POLE protein, are therefore unlikely to be associated with colon polyps or colon cancer. For these reasons, this variant has been classified as Likely Pathogenic for FILS syndrome. However, it is not likely to confer risk for autosomal dominant colonic adenomatous polyps and colon cancer.
Ambry Genetics RCV001022490 SCV001184236 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing Insufficient evidence
OMIM RCV000034317 SCV000058268 pathogenic Facial dysmorphism, immunodeficiency, livedo, and short stature 2012-12-17 no assertion criteria provided literature only

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