Submissions for variant NM_006231.4(POLE):c.1738C>A (p.His580Asn)

gnomAD frequency: 0.00011  dbSNP: rs371149234

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000657138	SCV000544080	uncertain significance	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 580 of the POLE protein (p.His580Asn). This variant is present in population databases (rs371149234, gnomAD 0.03%). 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: 405759). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx	RCV000657138	SCV000570789	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian or other cancers (Mandelker et al., 2017; Song et al., 2020); This variant is associated with the following publications: (PMID: 28873162, 20951805, 32546565)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000482170	SCV000731364	uncertain significance	not specified	2017-01-12	criteria provided, single submitter	clinical testing	The p.His580Asn variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 16/66736 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs371149234). Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, t he clinical significance of the p.His580Asn variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657138	SCV000889714	uncertain significance	not provided	2018-07-14	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000460401	SCV002581367	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657138	SCV004136754	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354877	SCV001549594	uncertain significance	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.His580Asn variant was not identified in the literature. It was identified in dbSNP (ID: rs371149234) as unknown significance and ClinVar (classified as uncertain significance by Invitae, GeneDx, and two other submitters). The variant was identified in control databases in 38 of 282892 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 35 of 129194 chromosomes (freq: 0.0003) and Latino in 3 of 35438 chromosomes (freq: 0.00009), while it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.His580 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657138	SCV001742541	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000657138	SCV001971279	uncertain significance	not provided		no assertion criteria provided	clinical testing