Submissions for variant NM_006231.4(POLE):c.226A>T (p.Lys76Ter)

dbSNP: rs1468404698

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001756182	SCV000819709	pathogenic	not provided	2023-07-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys76*) 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: 570917).
Ambry Genetics	RCV001014995	SCV001175776	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-24	criteria provided, single submitter	clinical testing	The p.K76* variant (also known as c.226A>T), located in coding exon 3 of the POLE gene, results from an A to T substitution at nucleotide position 226. This changes the amino acid from a lysine to a stop codon within coding exon 3. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001756182	SCV001986950	uncertain significance	not provided	2019-05-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge