Submissions for variant NM_006231.4(POLE):c.1007A>G (p.Asn336Ser)

gnomAD frequency: 0.00805  dbSNP: rs5744760

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759255	SCV000289233	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000759255	SCV000519163	benign	not provided	2018-06-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16741161, 17067213, 15766587, 25224212, 20951805)
Ambry Genetics	RCV000573616	SCV000671265	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.
Counsyl	RCV000230914	SCV000785512	benign	Colorectal cancer, susceptibility to, 12	2017-09-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000427188	SCV000806708	benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000427188	SCV000888483	benign	not specified	2021-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427188	SCV000918082	benign	not specified	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: POLE c.1007A>G (p.Asn336Ser) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 121118 control chromosomes in the ExAC database, including 5 homozygotes. The observed variant frequency is approximately 189.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1007A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000427188	SCV002550196	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000230914	SCV004016712	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000230914	SCV004018504	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354963	SCV001549700	likely benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Asn336Ser variant was identified in 2 of 1088 proband chromosomes (frequency: 0.002) from individuals or families with endometrial cancers (Billingsley 2015). The variant was also identified in dbSNP (ID: rs5744760) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics, Counsyl; as likely benign by GeneDx), and in MutDB. The variant was not identified in the Cosmic database. The variant was identified in control databases in 698 of 273020 chromosomes (10 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 615 of 23950 chromosomes (freq: 0.03), Other in 9 of 6364 chromosomes (freq: 0.001), Latino in 39 of 33222 chromosomes (freq: 0.001), European in 27 of 125476 chromosomes (freq: 0.0002), East Asian in 5 of 18714 chromosomes (freq: 0.0003), and South Asian in 3 of 29740 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Asn336 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000427188	SCV001807796	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000427188	SCV001920487	benign	not specified		no assertion criteria provided	clinical testing