Submissions for variant NM_006231.4(POLE):c.155G>A (p.Arg52Gln)

gnomAD frequency: 0.00004  dbSNP: rs372459649

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657077	SCV000556421	likely benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000657077	SCV000568363	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657077	SCV000601982	benign	not provided	2019-04-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001079124	SCV001483066	uncertain significance	Colorectal cancer, susceptibility to, 12	2020-11-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268099	SCV002550224	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402324	SCV002705615	likely benign	Hereditary cancer-predisposing syndrome	2022-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357956	SCV001553570	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg52Gln variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs372459649) “With Uncertain significance allele”, ClinVar (with conflicting interpretations of pathogenicity, submitters: likely benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano and uncertain significance by GeneDx), Clinvitae (2x), and in control databases in 54 of 277204 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 36 of 34418 chromosomes (freq: 0.001), European Non-Finnish in 3 of 126710 chromosomes (freq: 0.00002), Ashkenazi Jewish in 2 of 10150 chromosomes (freq: 0.0002), and South Asian in 12 of 30782 chromosomes (freq: 0.0004) while not observed in the African, East Asian and European Finnish populations. The p.Arg52 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Gln at this position to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.
PreventionGenetics, part of Exact Sciences	RCV004737542	SCV005351447	uncertain significance	POLE-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The POLE c.155G>A variant is predicted to result in the amino acid substitution p.Arg52Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD. ClinVar lists conflicting interpretations of pathogenicity ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/413598/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.