Submissions for variant NM_006231.4(POLE):c.1309G>A (p.Val437Met)

gnomAD frequency: 0.00001  dbSNP: rs115047349

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239213	SCV000297203	uncertain significance	not specified	2015-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569269	SCV000671482	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-24	criteria provided, single submitter	clinical testing	The p.V437M variant (also known as c.1309G>A), located in coding exon 13 of the POLE gene, results from a G to A substitution at nucleotide position 1309. The valine at codon 437 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001753714	SCV000772766	uncertain significance	not provided	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 437 of the POLE protein (p.Val437Met). This variant is present in population databases (rs115047349, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30306255). ClinVar contains an entry for this variant (Variation ID: 252659). 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 not expected to disrupt POLE protein function with a negative 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.
Counsyl	RCV000650917	SCV000786466	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001753714	SCV001985297	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ovarian cancer (Bonache et al., 2018); This variant is associated with the following publications: (PMID: 25228659, 30306255)
Myriad Genetics, Inc.	RCV000650917	SCV004018537	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	RCV000650917	SCV004203555	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753714	SCV004219075	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with ovarian cancer who also carried a truncating variant in the RECQL4 gene (PMID: 30306255 (2018)). The frequency of this variant in the general population, 0.000004 (1/251166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.