Submissions for variant NM_006231.4(POLE):c.2340G>A (p.Ser780=)

gnomAD frequency: 0.02051  dbSNP: rs5744822

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423956	SCV000518032	benign	not specified	2016-12-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589595	SCV000556418	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492210	SCV000581383	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	RCV000589595	SCV000698665	benign	not provided	2016-05-24	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.2340G>A (p.Ser780Ser) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing, while ESE finder predicts alterations to ESE binding sites. However, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2835/120810 (40 homozygotes, 1/42, frequency: 0.0234666), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLE variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000423956	SCV000806743	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000423956	SCV000889723	benign	not specified	2016-10-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000423956	SCV002550147	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000470624	SCV004016701	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000589595	SCV005237692	benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000492210	SCV005688810	benign	Hereditary cancer-predisposing syndrome	2025-01-20	criteria provided, single submitter	clinical testing	The synonymous variant NM_006231.4(POLE):c.2340G>A (p.Ser780=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380225 as of 2025-01-02). The p.Ser780= variant is observed in 107/5,008 (2.1366%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Ser780= variant is not predicted to disrupt an existing splice site. The p.Ser780= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign.
True Health Diagnostics	RCV000492210	SCV000788168	likely benign	Hereditary cancer-predisposing syndrome	2018-02-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357453	SCV001552931	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Ser780= variant was not identified in the literature nor was it identified in the Cosmic and MutDB. The variant was identified in dbSNP (ID: rs5744822) “With Benign ,Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x) and in control databases in 6661 (103 homozygous) of 275298 chromosomes at a frequency of 0.02 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 95 (1 homozygous) of 24026 chromosomes (freq: 0.004), Other in 168 (1 homozygous) of 6440 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34414 chromosomes (freq: 0.01), European Non-Finnish in 3414 (47 homozygous) of 126558 chromosomes (freq: 0.03), Ashkenazi Jewish in 163 (1 homozygous) of 10146 chromosomes (freq: 0.02), East Asian in 624 (12 homozygous) of 18856 chromosomes (freq: 0.03), European Finnish in 1026 (27 homozygous) of 24078 chromosomes (freq: 0.04), and South Asian in 757 (12 homozygous) of 30780 chromosomes (freq: 0.02). The p.Ser780= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 1 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 this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000423956	SCV001809689	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000423956	SCV001925973	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000423956	SCV002036729	benign	not specified		no assertion criteria provided	clinical testing