Submissions for variant NM_006231.4(POLE):c.3126G>A (p.Lys1042=)

gnomAD frequency: 0.02344  dbSNP: rs5744856

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444004	SCV000518492	benign	not specified	2015-11-11	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	RCV000586549	SCV000556383	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492620	SCV000581385	benign	Hereditary cancer-predisposing syndrome	2015-05-20	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	RCV000586549	SCV000698669	benign	not provided	2017-07-28	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.3126G>A (p.Lys1042Lys) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 795/121290 control chromosomes (19 homozygotes) at a frequency of 0.0065545, which is approximately 461 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000444004	SCV000806757	benign	not specified	2017-08-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000444004	SCV000888519	benign	not specified	2016-06-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586549	SCV001473588	benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000444004	SCV002550126	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080198	SCV004016702	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586549	SCV005237244	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000492620	SCV000788174	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355928	SCV001550956	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Lys1042= variant was identified in dbSNP (ID: rs5744856) “With Benign allele”. The variant was also identified in control databases in 1996 (73 homozygous) of 277210 chromosomes at a frequency of 0.007, 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 1809 (73 homozygous) of 24028 chromosomes (freq: 0.08), Other in 12 of 6466 chromosomes (freq: 0.002), Latino in 127 of 34420 chromosomes (freq: 0.004), European Non-Finnish in 26 of 126698 chromosomes (freq: 0.0002), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), and South Asian in 14 of 30782 chromosomes (freq: 0.0005), while not observed in the East Asian or European Finnish populations. The p.Lys1042= 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. The variant occurs outside of the splicing consensus sequence, although 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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	RCV000444004	SCV001809123	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000444004	SCV001921079	benign	not specified		no assertion criteria provided	clinical testing