Submissions for variant NM_002691.4(POLD1):c.301A>T (p.Ile101Phe)

gnomAD frequency: 0.00006  dbSNP: rs140858857

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471361	SCV000547674	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 101 of the POLD1 protein (p.Ile101Phe). This variant is present in population databases (rs140858857, gnomAD 0.003%). This missense change has been observed in individual(s) with Ewing's sarcoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 408120). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765472	SCV000896763	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001556112	SCV001777631	uncertain significance	not provided	2023-03-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of Ewing's sarcoma (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 26580448, 35620275)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268077	SCV002552085	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002268077	SCV003929291	uncertain significance	not specified	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.301A>T (p.Ile101Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251386 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.301A>T has been reported in the literature in one individuals affected with Ewing sarcoma (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26580448). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014: all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003925321	SCV004739702	uncertain significance	POLD1-related condition	2024-02-22	criteria provided, single submitter	clinical testing	The POLD1 c.301A>T variant is predicted to result in the amino acid substitution p.Ile101Phe. This variant has been reported in an individual with Ewing sarcoma (Table S4e. Zhang et al 2015. PubMed ID: 26580448). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/408120/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.