Submissions for variant NM_006231.4(POLE):c.274A>C (p.Ser92Arg)

gnomAD frequency: 0.00003  dbSNP: rs758382516

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001527857	SCV000289307	uncertain significance	not provided	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 92 of the POLE protein (p.Ser92Arg). This variant is present in population databases (rs758382516, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29987844). ClinVar contains an entry for this variant (Variation ID: 240443). 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.
Ambry Genetics	RCV000570743	SCV000671342	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-24	criteria provided, single submitter	clinical testing	The p.S92R variant (also known as c.274A>C), located in coding exon 3 of the POLE gene, results from an A to C substitution at nucleotide position 274. The serine at codon 92 is replaced by arginine, an amino acid with dissimilar properties. 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 well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.S92R remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000763820	SCV000894737	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001527857	SCV001739000	uncertain significance	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Observed in an individual with colorectal cancer (PMID: 29987844); 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: 29987844)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001527857	SCV002506157	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing	The POLE c.274A>C; p.Ser92Arg variant (rs758382516) is reported in the literature in an individual affected with colon cancer (Kayser 2018). This variant is also reported in ClinVar (Variation ID: 240443) and is found in the general population with an allele frequency of 0.0071% (20/282,850 alleles) in the Genome Aggregation Database. The serine at codon 92 is moderately conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.326). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Due to limited information, the clinical significance of the p.Ser92Arg variant is uncertain at this time.
Revvity Omics, Revvity	RCV001527857	SCV003809184	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004546465	SCV005042879	uncertain significance	Colorectal cancer, susceptibility to, 12		criteria provided, single submitter	clinical testing	The missense c.274A>C p.Ser92Arg variant in the POLE gene has been observed in individuals with colorectal cancer Kayser 2018. This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Serine at position 92 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser92Arg in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics	RCV001527857	SCV005192075	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004541427	SCV004762285	uncertain significance	POLE-related disorder	2024-01-04	no assertion criteria provided	clinical testing	The POLE c.274A>C variant is predicted to result in the amino acid substitution p.Ser92Arg. This variant has been reported in an individual with suspected Lynch syndrome (Table 2, Kayser et al. 2018. PubMed ID: 29987844). No further information regarding segregation studies available that would help determine the pathogenicity of this variant. This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD. It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240443/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.