Submissions for variant NM_002691.4(POLD1):c.653G>A (p.Arg218His)

gnomAD frequency: 0.00045  dbSNP: rs150010804

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079679	SCV000287647	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657073	SCV000293404	uncertain significance	not provided	2019-01-03	criteria provided, single submitter	clinical testing	This variant is denoted POLD1 c.653G>A at the cDNA level, p.Arg218His (R218H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLD1 Arg218His was observed at an allele frequency of 0.42% (40/9490) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLD1 Arg218His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000236875	SCV000596495	benign	not specified	2021-05-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568154	SCV000670935	benign	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236875	SCV001623329	benign	not specified	2021-04-25	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.653G>A (p.Arg218His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 242300 control chromosomes. The observed variant frequency is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.653G>A 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 (VUS, n=3, benign, n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657073	SCV002047718	uncertain significance	not provided	2021-03-31	criteria provided, single submitter	clinical testing	The POLD1 c.653G>A; p.Arg218His variant (rs150010804), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 239365). This variant is found in the general population with an overall allele frequency of 0.03% (87/275,000 alleles) in the Genome Aggregation Database. The arginine at codon 218 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.190). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, based on the available information, the clinical significance of this variant is uncertain. References: Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001079679	SCV002525961	uncertain significance	Colorectal cancer, susceptibility to, 10	2021-07-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568154	SCV002534697	benign	Hereditary cancer-predisposing syndrome	2020-12-29	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004541401	SCV004797595	likely benign	POLD1-related disorder	2020-01-21	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355957	SCV001550991	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The POLD1 p.Arg218His variant was not identified in the literature nor was it identified in the Cosmic and MutDB. The variant was identified in the following databases: dbSNP (ID: rs150010804) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Invitae and uncertain significance by GeneDx, Ambry Genetics and Genetic Services Laboratory (University of Chicago)), Clinvitae (3x), and in control databases in 78 of 268790 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23620 chromosomes (freq: 0.00004), Other in 3 of 6274 chromosomes (freq: 0.0005), Latino in 1 of 33644 chromosomes (freq: 0.00003), European Non-Finnish in 33 of 122214 chromosomes (freq: 0.0003), Ashkenazi Jewish in 40 of 9490 chromosomes (freq: 0.004); it was not in the East Asian, European Finnish and South Asian populations. The p.Arg218 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His 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, 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.