ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1114G>A (p.Glu372Lys)

dbSNP: rs960226186
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000464011 SCV000547650 uncertain significance Colorectal cancer, susceptibility to, 10 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 372 of the POLD1 protein (p.Glu372Lys). This variant is not present in population databases (gnomAD no frequency). 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: 408097). 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.
Ambry Genetics RCV001017369 SCV001178443 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing The p.E372K variant (also known as c.1114G>A), located in coding exon 8 of the POLD1 gene, results from a G to A substitution at nucleotide position 1114. The glutamic acid at codon 372 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001574450 SCV001801270 uncertain significance not provided 2022-10-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 20951805)
Genetic Services Laboratory, University of Chicago RCV001821262 SCV002070146 uncertain significance not specified 2020-02-24 criteria provided, single submitter clinical testing DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.1114G>A, in exon 9 that results in an amino acid change, p.Glu372Lys. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has also not been described in population databases (gnomAD, ExAC). The p.Glu372Lys change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu372Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu372Lys change remains unknown at this time.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001821262 SCV002551901 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821262 SCV003922874 uncertain significance not specified 2023-03-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000464011 SCV004203486 uncertain significance Colorectal cancer, susceptibility to, 10 2024-03-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005027510 SCV005650293 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120 2024-03-07 criteria provided, single submitter clinical testing

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