Submissions for variant NM_199420.4(POLQ):c.5158C>T (p.Leu1720Phe)

gnomAD frequency: 0.00153  dbSNP: rs139982859

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004036706	SCV002644837	uncertain significance	not specified	2024-09-04	criteria provided, single submitter	clinical testing	The p.L1720F variant (also known as c.5158C>T), located in coding exon 16 of the POLQ gene, results from a C to T substitution at nucleotide position 5158. The leucine at codon 1720 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. 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 this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354364	SCV001548963	likely benign	not provided		no assertion criteria provided	clinical testing	The POLQ p.Leu1720Phe variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139982859) and in control databases in 514 of 280978 chromosomes (1 homozygous) at a frequency of 0.001829 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 146 of 24954 chromosomes (freq: 0.005851), European (non-Finnish) in 335 of 128436 chromosomes (freq: 0.002608), Other in 18 of 7166 chromosomes (freq: 0.002512), Ashkenazi Jewish in 12 of 10322 chromosomes (freq: 0.001163) and African in 3 of 24948 chromosomes (freq: 0.00012), but was not observed in the Latino, East Asian or South Asian populations. The p.Leu1720 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003963240	SCV004778247	likely benign	POLQ-related disorder	2019-10-28	no assertion criteria provided	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).