Submissions for variant NM_006231.4(POLE):c.1016A>T (p.Asp339Val)

dbSNP: rs1060500865

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679595	SCV000544153	uncertain significance	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 339 of the POLE protein (p.Asp339Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405828). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000570445	SCV000671428	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-13	criteria provided, single submitter	clinical testing	The p.D339V variant (also known as c.1016A>T), located in coding exon 10 of the POLE gene, results from an A to T substitution at nucleotide position 1016. The aspartic acid at codon 339 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000471158	SCV000786366	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-04-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679595	SCV000806709	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679595	SCV001134672	uncertain significance	not provided	2019-02-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192845	SCV001361238	uncertain significance	not specified	2019-04-18	criteria provided, single submitter	clinical testing	Variant summary: POLE c.1016A>T (p.Asp339Val) results in a non-conservative amino acid change located in the exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245574 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1016A>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000679595	SCV001875067	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient suspected of having Hereditary Breast and Ovarian Cancer (PMID: 38136308); This variant is associated with the following publications: (PMID: 20951805, 38136308, 29056344)
Myriad Genetics, Inc.	RCV000471158	SCV004018527	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000471158	SCV004203539	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-03-07	criteria provided, single submitter	clinical testing