Submissions for variant NM_006231.4(POLE):c.5636G>A (p.Arg1879His)

gnomAD frequency: 0.00018  dbSNP: rs145621558

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455415	SCV000540089	uncertain significance	not specified	2016-10-13	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant not in HGMD or ClinVar. MaxMAF is 0.11% AA not conserved in mammals - His seen in 6 non-mammals.
Invitae	RCV003539892	SCV000556300	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000455415	SCV000569856	uncertain significance	not specified	2016-04-04	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.5636G>A at the cDNA level, p.Arg1879His (R1879H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg1879His was observed with an allele frequency of 0.4% (5/1322) in the African populations in 1000 Genomes. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. POLE Arg1879His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg1879His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575608	SCV000671400	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-18	criteria provided, single submitter	clinical testing	The p.R1879H variant (also known as c.5636G>A), located in coding exon 41 of the POLE gene, results from a G to A substitution at nucleotide position 5636. The arginine at codon 1879 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs145621558. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.94% (1/106) African-American SW alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (3/13006) total alleles studied, having been observed in 0.07% (3/4406) African American alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.R1879H remains unclear.
Baylor Genetics	RCV001788222	SCV002030090	uncertain significance	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000575608	SCV002536898	likely benign	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003418146	SCV004114929	uncertain significance	POLE-related condition	2022-11-30	criteria provided, single submitter	clinical testing	The POLE c.5636G>A variant is predicted to result in the amino acid substitution p.Arg1879His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133214642-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/403332). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000464959	SCV004171517	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-10-25	criteria provided, single submitter	clinical testing	The POLE c.5636G>A (p.Arg1879His) missense change has a maximum subpopulation frequency of 0.10% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.