Submissions for variant NM_006231.4(POLE):c.91G>T (p.Ala31Ser)

gnomAD frequency: 0.01320  dbSNP: rs34047482

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588915	SCV000262458	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000205587	SCV000489133	benign	Colorectal cancer, susceptibility to, 12	2016-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000433484	SCV000517990	benign	not specified	2015-11-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000562087	SCV000671223	benign	Hereditary cancer-predisposing syndrome	2015-05-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588915	SCV000698690	benign	not provided	2016-05-24	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.91G>T (p.Ala31Ser) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 1485/121338 control chromosomes (20 homozygotes) at a frequency of 0.0122385, which is approximately 862 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000433484	SCV000806861	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000433484	SCV000889797	benign	not specified	2016-09-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588915	SCV001159489	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000433484	SCV002550228	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000205587	SCV004016695	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000588915	SCV005237713	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000562087	SCV000788196	likely benign	Hereditary cancer-predisposing syndrome	2018-01-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357646	SCV001553173	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Ala31Ser variant was not identified in the literature nor was it identified in the Cosmic, databases. The variant was identified in dbSNP (ID: rs34047482) as With Benign allele, ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics), Clinvitae (classified as benign by Invitae, ClinVar), MutDB, databases. The variant was identified in control databases in 3418 of 277182 chromosomes (47 homozygous) at a frequency of 0.012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 85 of 24036 chromosomes (freq: 0.004), Other in 87 of 6464 chromosomes (freq: 0.014), Latino in 214 of 34418 chromosomes (freq: 0.006), EuropeanNon-Finnish in 2527 of 126668 chromosomes (freq: 0.02), AshkenaziJewish in 13 of 10150 chromosomes (freq: 0.0013), EastAsian in 1 of 18870 chromosomes (freq: 0.00005), EuropeanFinnish in 196 of 25794 chromosomes (freq: 0.008), and SouthAsian in 295 of 30782 chromosomes (freq: 0.01). The p.Ala31 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 addition, GeneDx classified the variant as benign based on following criteria: “it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease”. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588915	SCV001799254	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000433484	SCV001809018	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000433484	SCV001924978	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588915	SCV001932300	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000433484	SCV001956022	benign	not specified		no assertion criteria provided	clinical testing