Submissions for variant NM_002691.4(POLD1):c.2429C>T (p.Ala810Val)

gnomAD frequency: 0.00004  dbSNP: rs765981178

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471609	SCV000547671	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 810 of the POLD1 protein (p.Ala810Val). This variant is present in population databases (rs765981178, gnomAD 0.01%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 26748215). ClinVar contains an entry for this variant (Variation ID: 408118). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLD1 protein function with a positive 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	RCV000567249	SCV000674266	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-06	criteria provided, single submitter	clinical testing	The p.A810V variant (also known as c.2429C>T), located in coding exon 19 of the POLD1 gene, results from a C to T substitution at nucleotide position 2429. The alanine at codon 810 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000471609	SCV000785423	uncertain significance	Colorectal cancer, susceptibility to, 10	2017-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781762	SCV000920064	likely benign	not specified	2018-04-06	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.2429C>T (p.Ala810Val) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although there are POLD1 pseudogenes that may complicate NGS mapping, BLAT analysis shows that the variant does not lie within a large pseudogene region, suggesting it is a true variant. c.2429C>T has been reported in the literature in one individual affected with endometrial cancer. This report does not provide unequivocal conclusions about an association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001653828	SCV001870993	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with endometrial or breast cancer, as well as individuals with autism spectrum disorder (PMID: 26748215, 30306255, 31133750, 35982159); Also known as c.2507C>T; p.(Ala836Val); This variant is associated with the following publications: (PMID: 30306255, 25363768, 26748215, 21796119, 34011629, 31785789, 20951805, 35982159, 33057194, 31133750)
Sema4, Sema4	RCV000567249	SCV002534633	benign	Hereditary cancer-predisposing syndrome	2020-11-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781762	SCV004243001	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005018777	SCV005650310	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-05-21	criteria provided, single submitter	clinical testing