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

dbSNP: rs147911699

Total submissions: 17

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
Labcorp Genetics (formerly Invitae), Labcorp	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.
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235439	SCV005089937	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657103	SCV005409981	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	BP4
True Health Diagnostics	RCV000562731	SCV000805289	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529014	SCV000806488	likely benign	POLD1-related disorder	2023-05-04	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).
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.