Submissions for variant NM_002691.4(POLD1):c.1686+10C>T

gnomAD frequency: 0.00008  dbSNP: rs372652150

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204952	SCV000261748	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000418399	SCV000524704	likely benign	not specified	2017-05-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418399	SCV001623343	likely benign	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.1686+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 241148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1686+10C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000418399	SCV002071168	likely benign	not specified	2019-09-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357668	SCV001553198	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 c.1686+10C>T variant was not identified in the literature. The variant was identified dbSNP (rs372652150) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae and GeneDx). The variant was identified in control databases in 11 of 267,230 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23,800 chromosomes (freq: 0.00008), European in 7 of 123,466 chromosomes (freq: 0.00006), East Asian in 1 of 18,704 chromosomes (freq: 0.00005), and South Asian in 1 of 29,814 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, or Finnish, populations. The variant occurs at a non-highly conserved nucleotide 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.