Submissions for variant NM_006231.4(POLE):c.3913G>A (p.Gly1305Arg)

gnomAD frequency: 0.00002  dbSNP: rs563990655

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478117	SCV000289353	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000478117	SCV000568976	uncertain significance	not provided	2018-10-25	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.3913G>A at the cDNA level, p.Gly1305Arg (G1305R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has been observed in at least one individual with advanced cancer (Mandelker 2017). POLE Gly1305Arg was observed at an allele frequency of 0.33% (104/30,762) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLE Gly1305Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Sema4, Sema4	RCV002257579	SCV002536830	likely benign	Hereditary cancer-predisposing syndrome	2021-03-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493545	SCV004243491	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354616	SCV001549275	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Gly1305Arg variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals or families with advanced cancer (Mandelker 2017). The variant was also identified in dbSNP (ID: rs563990655) as "With Uncertain significance allele" and in ClinVar (classified as likely benign by Invitae; and as uncertain significance by GeneDx). The variant was identified in control databases in 116 of 274180 chromosomes (1 homozygous) at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23490 chromosomes (freq: 0.00004), Other in 2 of 6406 chromosomes (freq: 0.0003), Latino in 3 of 34380 chromosomes (freq: 0.00009), European in 5 of 124574 chromosomes (freq: 0.00004), Ashkenazi Jewish in 1 of 10048 chromosomes (freq: 0.0001), and South Asian in 104 of 30762 chromosomes (1 homozygous, freq: 0.003; increasing the likelihood this could be a low frequency benign variant); it was not observed in the East Asian or Finnish populations. The p.Gly1305 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.