Submissions for variant NM_006231.4(POLE):c.555C>T (p.Asp185=)

gnomAD frequency: 0.00004  dbSNP: rs763871536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204352	SCV000262310	likely benign	not provided	2025-01-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000204352	SCV000520743	likely benign	not provided	2020-06-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573971	SCV000671457	likely benign	Hereditary cancer-predisposing syndrome	2015-08-10	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000204352	SCV001134934	benign	not provided	2018-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427161	SCV001361236	benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: POLE c.555C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 277132 control chromosomes (gnomAD). The observed variant frequency is approximately 5 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.555C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001085060	SCV004016698	likely benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000204352	SCV004136763	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7