Submissions for variant NM_002691.4(POLD1):c.14G>A (p.Arg5Gln)

gnomAD frequency: 0.00006  dbSNP: rs748471297

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475642	SCV000547603	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 5 of the POLD1 protein (p.Arg5Gln). This variant is present in population databases (rs748471297, gnomAD 0.02%). 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: 408051). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759935	SCV000889648	uncertain significance	not provided	2019-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000759935	SCV001792472	uncertain significance	not provided	2024-04-09	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759935	SCV003799582	uncertain significance	not provided	2022-07-22	criteria provided, single submitter	clinical testing	The POLD1 c.14G>A; p.Arg5Gln variant (rs748471297), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 408051). This variant is found in the general population with an overall allele frequency of 0.0048% (13/268550 alleles) in the Genome Aggregation Database. The arginine at codon 5 is highly conserved, but computational analyses predict that this variant is neutral (REVEL: 0.086). 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, given the lack of clinical and functional data, the 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.
Ambry Genetics	RCV004943890	SCV005476228	likely benign	Hereditary cancer-predisposing syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV005018772	SCV005650270	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-06-10	criteria provided, single submitter	clinical testing