Submissions for variant NM_002691.4(POLD1):c.581C>G (p.Ser194Cys)

gnomAD frequency: 0.00061  dbSNP: rs144656348

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084000	SCV000287638	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506634	SCV000601948	likely benign	not specified	2017-04-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567879	SCV000670915	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-19	criteria provided, single submitter	clinical testing	The p.S194C variant (also known as c.581C>G), located in coding exon 4 of the POLD1 gene, results from a C to G substitution at nucleotide position 581. The serine at codon 194 is replaced by cysteine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs144656348. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.54% (1/186) Finnish alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S194C remains unclear.
GeneDx	RCV000679522	SCV000715942	likely benign	not provided	2020-07-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679522	SCV000806551	likely benign	not provided	2017-05-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567879	SCV002534689	benign	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506634	SCV002551878	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003128399	SCV003804807	likely benign	See cases	2022-12-21	criteria provided, single submitter	clinical testing	ACMG categories: BS2,BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356988	SCV001552299	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLD1 p.Ser194Cys variant was not identified in the literature. The variant was identified in dbSNP (ID: rs144656348) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae, GeneDx and two other submitters; as uncertain significance by Ambry Genetics), and in LOVD 3.0 (1x) .The variant was identified in control databases in 178 of 273686 chromosomes (1 homozygous) at a frequency of 0.0007 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: Other in 8 of 6358 chromosomes (freq: 0.001), Latino in 1 of 34170 chromosomes (freq: 0.00003), European in 68 of 124668 chromosomes (freq: 0.0006), European Finnish in 84 of 25520 chromosomes (freq: 0.003), and South Asian in 17 of 30346 chromosomes (freq: 0.0006), while the variant was not observed in the African, Ashkenazi Jewish, and East Asian, populations. The p.Ser194 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.