Submissions for variant NM_006231.4(POLE):c.2510T>C (p.Phe837Ser)

gnomAD frequency: 0.00028  dbSNP: rs139182500

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657113	SCV000544188	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657113	SCV000569231	likely benign	not provided	2021-06-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with advanced cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 28873162, 29338072)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478239	SCV000602004	uncertain significance	not specified	2016-10-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573358	SCV000671291	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-15	criteria provided, single submitter	clinical testing	<span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px">The p.F837S variant (also known as c.2510T>C), located in coding exon 22 of the POLE gene, results from a T to C substitution at nucleotide position 2510. The phenylalanine at codon 837 is replaced by serine, an amino acid with highly dissimilar properties. This variant was previously reported in the SNPDatabase as rs139182500. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.03% (4/13006) total alleles studied and 0.05% (4/8600) European American alleles. This amino acid position is well conserved through mammalianspecies. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Baylor Genetics	RCV001336930	SCV001530461	uncertain significance	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-06-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV000478239	SCV002067046	uncertain significance	not specified	2020-09-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.2510T>C, in exon 22 that results in an amino acid change, p.Phe837Ser. This sequence change does not appear to have been previously described in patients with POLE-related disorders and has been described in the gnomAD database with a frequency of 0.45% in the Ashkenazi Jewish sub-population (dbSNP rs139182500). The p.Phe837Ser change affects a moderately conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Phe837Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe837Ser change remains unknown at this time.
Sema4, Sema4	RCV000573358	SCV002536785	likely benign	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001079698	SCV003928067	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-03-27	criteria provided, single submitter	clinical testing	The POLE c.2510T>C (p.Phe837Ser) missense change has a maximum founder subpopulation frequency of 0.45% and a maximum non-founder subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000478239	SCV004027343	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354850	SCV001549562	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLE p.Phe837Ser variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from an individual with an unspecified cancer (Mandelker 2017). The variant was identified in dbSNP (rs139182500) as “with uncertain significance allele” and ClinVar (interpreted as "uncertain signficance" by Ambry Genetics and 2 others and "likely benign" by Invitae). The variant was identified in control databases in 72 of 277,116 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6462 chromosomes (freq: 0.0005), Latino in 10 of 34,420 chromosomes (freq: 0.0003), European in 16 of 126,680 chromosomes (freq: 0.0001), Ashkenazi Jewish in 43 of 10,150 chromosomes (freq: 0.004); it was not observed in the African, East Asian, Finnish, and South Asian populations. The p.Phe837 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	RCV004539936	SCV004785294	likely benign	POLE-related disorder	2022-03-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).