Submissions for variant NM_006231.4(POLE):c.5761A>G (p.Asn1921Asp)

gnomAD frequency: 0.00002  dbSNP: rs771980261

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760026	SCV000544179	uncertain significance	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1921 of the POLE protein (p.Asn1921Asp). This variant is present in population databases (rs771980261, gnomAD 0.005%). 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: 405854). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000600383	SCV000712876	uncertain significance	not specified	2017-02-26	criteria provided, single submitter	clinical testing	The p.Asn1921Asp variant in POLE has not been previously reported in individuals with colorectal cancer but has been identified in 3/66620 of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs771980261). Computational prediction tools and conservation analysis sugge st that the p.Asn1921Asp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical s ignificance of the p.Asn1921Asp variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760026	SCV000889774	uncertain significance	not provided	2018-01-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765047	SCV000896244	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000760026	SCV001827071	uncertain significance	not provided	2024-03-12	criteria provided, single submitter	clinical testing	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: 34326862, 35534704)
Ambry Genetics	RCV004943868	SCV005479472	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing	The p.N1921D variant (also known as c.5761A>G), located in coding exon 42 of the POLE gene, results from an A to G substitution at nucleotide position 5761. The asparagine at codon 1921 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005004169	SCV005633678	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	2024-01-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357597	SCV001553110	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Asn1921Asp variant was not identified in the literature, nor was it identified in Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs771980261) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), and Clinvitae. The variant was identified in control databases in 8 of 277116 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Latino in 1 of 34372 chromosomes (freq: 0.00003), European in 6 of 126678 chromosomes (freq: 0.0001); but not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1921 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.