Submissions for variant NM_006231.4(POLE):c.3583_4150-1613del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067551	SCV001232618	uncertain significance	Colorectal cancer, susceptibility to, 12	2019-12-20	criteria provided, single submitter	clinical testing	This variant is a complex sequence change that deletes the genomic region encompassing exons 30-32 and inserts another 47 nucleotides at the intron 29-exon 30 boundary (c.3583_4150-1613delins47) of the POLE gene. It is expected to result in a frameshift (p.Val1195Trpfs*951) and disrupt the last 1092 amino acids of the POLE protein. This variant has not been reported in the literature in individuals with POLE-related disease. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE/POLD1 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/POLD1 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.