Submissions for variant NM_006231.4(POLE):c.1191C>G (p.Tyr397Ter)

gnomAD frequency: 0.00001  dbSNP: rs1208085896

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657728	SCV000779478	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.1191C>G at the cDNA level and p.Tyr397Ter (Y397X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG). This variant has not, to our knowledge, been reported in the literature. 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. Based on current evidence, we consider this variant to be of uncertain 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657728	SCV000964445	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr397*) 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 present in population databases (no rsID available, gnomAD 0.006%). 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: 545996). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002334220	SCV002641825	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-09	criteria provided, single submitter	clinical testing	The p.Y397* variant (also known as c.1191C>G), located in coding exon 12 of the POLE gene, results from a C to G substitution at nucleotide position 1191. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. 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 (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).