Submissions for variant NM_006231.4(POLE):c.2683G>A (p.Ala895Thr)

gnomAD frequency: 0.00024  dbSNP: rs201115064

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657053	SCV000322161	uncertain significance	not provided	2024-08-27	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: 25529843, 24410847, 28615371, 29987844, 30194485, 35264596, 20951805, 25860647, 25079317, 25642631, 25559809, 23636398, 21157497, 26822575, 29120461)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657053	SCV000543990	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255380	SCV000596499	uncertain significance	not specified	2017-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657053	SCV000602013	uncertain significance	not provided	2019-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569257	SCV000671313	likely benign	Hereditary cancer-predisposing syndrome	2024-02-27	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000255380	SCV000712561	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	The p.Ala895Thr variant in POLE has been reported in 2 individuals with colorect al adenomatous polyposis with an attenuated phenotype (Spier 2015). This variant has also been identified in 47/66724 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201115064). Com putational prediction tools and conservation analysis suggest that the p.Ala895T hr variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.A la895Thr variant is uncertain.
Counsyl	RCV000472688	SCV000785069	uncertain significance	Colorectal cancer, susceptibility to, 12	2017-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765065	SCV000896262	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV003492020	SCV001138889	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657053	SCV001148895	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657053	SCV002009590	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569257	SCV002536791	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255380	SCV002550136	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000472688	SCV002580366	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-06-09	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000657053	SCV005197239	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000569257	SCV000788171	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357604	SCV001553119	uncertain significance	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Ala895Thr variant was identified in 2 of 532 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Spier 2015). The variant was also identified in dbSNP (ID: rs201115064) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters). The variant was identified in control databases in 84 of 277182 chromosomes at a frequency of 0.0003 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: Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34418 chromosomes (freq: 0.00006), European in 66 of 126678 chromosomes (freq: 0.0005), Finnish in 15 of 25788 chromosomes (freq: 0.0006), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ala895 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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	RCV004535237	SCV004723856	uncertain significance	POLE-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The POLE c.2683G>A variant is predicted to result in the amino acid substitution p.Ala895Thr. This variant has been reported in two unrelated patients with a history of sporadic polyposis, but segregation information was not provided (Spier et al. 2015. PubMed ID: 25529843). This variant was also reported in an individual with a history of colorectal cancer who was also positive for a variant in POLD1 (Patient 25, Kayser et al. 2018. PubMed ID: 29987844). This variant was reported in an individual with colorectal adenoma/carcinoma (Spier et al. 2015. PubMed ID: 25529843; Kayser et al. 2018. PubMed ID: 29987844; Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.052% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has interpretations in ClinVar as a variant of uncertain significance and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/265355/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.