Submissions for variant NM_002691.4(POLD1):c.203G>A (p.Gly68Glu)

gnomAD frequency: 0.00001  dbSNP: rs144707871

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233715	SCV000287548	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 68 of the POLD1 protein (p.Gly68Glu). This variant is present in population databases (rs144707871, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239267). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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.
GeneDx	RCV000657137	SCV000570788	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000477990	SCV000601899	uncertain significance	not specified	2016-08-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000477990	SCV000712718	uncertain significance	not specified	2016-12-08	criteria provided, single submitter	clinical testing	The p.Gly68Glu variant in POLD1 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/66138 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs144707871). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. This var iant is located in the first base of the exon (which is part of the 3? splice re gion) but computational tools do not suggest a significant impact on splicing. H owever, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly68Glu variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV000765468	SCV000896759	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2018-10-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000233715	SCV002012369	uncertain significance	Colorectal cancer, susceptibility to, 10	2021-08-10	criteria provided, single submitter	clinical testing	The POLD1 c.203G>A (p.Gly68Glu) missense change has a maximum subpopulation frequency of 0.0071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/19-50902628-G-A). Four of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. In addition, algorithms that predict the impact of sequence changes on splicing indicate that this change is unlikely to significantly impact splicing. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657137	SCV003799576	uncertain significance	not provided	2022-04-14	criteria provided, single submitter	clinical testing	The POLD1 c.203G>A; p.Gly68Glu variant (rs144707871), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239267). This variant is found in the general population with an overall allele frequency of 0.003% (8/250932 alleles) in the Genome Aggregation Database. The glycine at codon 68 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.107). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490 Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343
PreventionGenetics, part of Exact Sciences	RCV003390991	SCV004120489	uncertain significance	POLD1-related condition	2023-07-20	criteria provided, single submitter	clinical testing	The POLD1 c.203G>A variant is predicted to result in the amino acid substitution p.Gly68Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50902628-G-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/239267/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000657137	SCV004140549	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	POLD1: BP4