Submissions for variant NM_006231.4(POLE):c.4857_4858insA (p.Gly1620fs)

dbSNP: rs1432073374

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657327	SCV000779058	uncertain significance	not provided	2017-05-11	criteria provided, single submitter	clinical testing	This insertion of one nucleotide in POLE is denoted c.4857_4858insA at the cDNA level and p.Gly1620ArgfsX74 (G1620RfsX74) at the protein level. The normal sequence, with the base that is inserted in brackets, is CTAT[insA]GGGGT. The insertion causes a frameshift which changes a Glycine to an Arginine at codon 1620, and creates a premature stop codon at position 74 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. However, 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 2014), 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. Based on current evidence, we consider this variant be of uncertain significance with respect to cancer. A recessive disease associated with one POLE variant has been reported in the literature. In one large consanguineous family, 11 affected relatives with a syndrome called FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) were all found to be homozygous for a 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657327	SCV004490153	pathogenic	not provided	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1620Argfs*74) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is not present in population databases (gnomAD no frequency). 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: 545787). For these reasons, this variant has been classified as Pathogenic.