ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.208G>T (p.Val70Phe)

dbSNP: rs147911699
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000210898 SCV000264608 uncertain significance Carcinoma of colon 2016-01-01 criteria provided, single submitter research
Invitae RCV000228225 SCV000287552 likely benign Colorectal cancer, susceptibility to, 10 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000657103 SCV000293719 likely benign not provided 2021-01-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Ghazani 2017); This variant is associated with the following publications: (PMID: 28125075)
Counsyl RCV000228225 SCV000489065 uncertain significance Colorectal cancer, susceptibility to, 10 2016-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235439 SCV000601903 benign not specified 2020-04-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562731 SCV000670871 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.
PreventionGenetics, part of Exact Sciences RCV004529014 SCV000806488 likely benign POLD1-related disorder 2023-05-04 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).
Fulgent Genetics, Fulgent Genetics RCV000765469 SCV000896760 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000228225 SCV001141127 uncertain significance Colorectal cancer, susceptibility to, 10 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000657103 SCV001474183 uncertain significance not provided 2020-04-03 criteria provided, single submitter clinical testing The POLD1 c.208G>T; p.Val70Phe variant (rs147911699) is reported in the literature in an individual with colon cancer (Ghazani 2017). This variant is also reported in ClinVar (Variation ID: 225288). It is found in the general population with an overall allele frequency of 0.03% (89/282506 alleles) in the Genome Aggregation Database. The valine at codon 70 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Ghazani AA et al. Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. Genet Med. 2017 Jul;19(7):787-795.
Genetic Services Laboratory, University of Chicago RCV000235439 SCV002065982 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.208G>T, in exon 3 that results in an amino acid change, p.Val70Phe. This sequence change has been described in the gnomAD database with a frequency of 0.062% in the European sub-population (dbSNP rs147911699). The p.Val70Phe change has been identified in an individual with colon cancer (PMID: 28125075). The p.Val70Phe change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is not known to be functional. The p.Val70Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val70Phe change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000228225 SCV003842998 uncertain significance Colorectal cancer, susceptibility to, 10 2023-01-17 criteria provided, single submitter clinical testing The POLD1 c.208G>T (p.Val70Phe) missense change has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV000657103 SCV004698776 likely benign not provided 2024-01-01 criteria provided, single submitter clinical testing POLD1: BP4, BS1
True Health Diagnostics RCV000562731 SCV000805289 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000657103 SCV000840296 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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