Submissions for variant NM_006231.4(POLE):c.691C>T (p.Arg231Cys)

gnomAD frequency: 0.00023  dbSNP: rs146592584

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657130	SCV000289487	likely benign	not provided	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657130	SCV000569809	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of colon and other cancers (PMID: 28873162, 29212164, 34326862, 35430768); 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: 29212164, 28873162, 26193622, 2212164, 26251183, 34326862, 35430768)
PreventionGenetics, part of Exact Sciences	RCV000657130	SCV000806852	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657130	SCV000889791	uncertain significance	not provided	2020-05-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000478783	SCV000967515	uncertain significance	not specified	2018-10-18	criteria provided, single submitter	clinical testing	The p.Arg231Cys variant in POLE has been reported in the literature in two indiv iduals with colorectal cancer (Raskin 2017, Mandelker 2017) and has also been re ported by other clinical laboratories in ClinVar (Variation ID: 240623). This va riant has also been identified in 37/126680 European chromosomes by gnomAD (http ://gnomad.broadinstitute.org). Computational prediction tools and conservation a nalysis suggest that the p.Arg231Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, th e clinical significance of the p.Arg231Cys variant is uncertain. ACMG/AMP Criter ia applied: PP3, PS4_Supporting.
Sema4, Sema4	RCV002257590	SCV002536935	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000478783	SCV002550208	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000229088	SCV002579299	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-12-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002257590	SCV005481506	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	The p.R231C variant (also known as c.691C>T), located in coding exon 7 of the POLE gene, results from a C to T substitution at nucleotide position 691. The arginine at codon 231 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been observed in the literature in multiple individuals from cancer cohorts (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463; Bhai P et al. Front Genet, 2021 Jul;12:698595; Adamson AW et al. J Ovarian Res, 2023 Jul;16:141). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005008201	SCV005633771	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2023-12-28	criteria provided, single submitter	clinical testing