Submissions for variant NM_006231.4(POLE):c.6274G>A (p.Gly2092Ser)

gnomAD frequency: 0.00012  dbSNP: rs757559474

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001597141	SCV000544020	uncertain significance	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2092 of the POLE protein (p.Gly2092Ser). This variant is present in population databases (rs757559474, gnomAD 0.04%). This missense change has been observed in individual(s) with POLE-related conditions (PMID: 28125075, 28873162, 34326862). ClinVar contains an entry for this variant (Variation ID: 405705). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001597141	SCV001830726	uncertain significance	not provided	2024-04-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28125075, 34326862, 31034466, 28873162)
Sema4, Sema4	RCV002258901	SCV002536910	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004533157	SCV004114416	uncertain significance	POLE-related disorder	2023-02-02	criteria provided, single submitter	clinical testing	The POLE c.6274G>A variant is predicted to result in the amino acid substitution p.Gly2092Ser. This variant was reported in an individual with colon cancer; however, pathogenicity was not established (Ghazani et al 2017. PubMed ID: 28125075). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133208957-C-T) and is categorized as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405705). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596184	SCV005090425	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002258901	SCV005478824	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-29	criteria provided, single submitter	clinical testing	The p.G2092S variant (also known as c.6274G>A), located in coding exon 45 of the POLE gene, results from a G to A substitution at nucleotide position 6274. The glycine at codon 2092 is replaced by serine, an amino acid with similar properties. This variant has been reported in an individual with colorectal cancer (Ghazani AA et al. Genet Med, 2017 Jul;19:787-795). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.
Fulgent Genetics, Fulgent Genetics	RCV005010343	SCV005634225	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2024-06-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358166	SCV001553835	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Gly2092Ser variant was identified in 1 of 330 proband chromosomes (frequency: 0.003) from individuals or families with metastatic lung or colon cancer, who were undergoing whole exome sequencing, with the affected individual having CRC (Ghazani 2017). The variant was identified in dbSNP (ID: rs757559474) “With Uncertain significance allele”, and ClinVar (classified as uncertain significance by Invitae). The variant was also identified in control databases in 13 of 277140 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 10 of 24026 chromosomes (freq: 0.0004) and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Gly2092 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ser to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.