Submissions for variant NM_002691.4(POLD1):c.835_837del (p.Glu279del)

dbSNP: rs746341854

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562268	SCV000670994	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-01	criteria provided, single submitter	clinical testing	The c.835_837delGAG variant (also known as p.E279del) is located in coding exon 6 of the POLD1 gene. This variant results from an in-frame GAG deletion at nucleotide positions 835 to 837. This results in the in-frame deletion of a glutamic acid at codon 279. This amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000645839	SCV000767594	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-19	criteria provided, single submitter	clinical testing	This variant, c.835_837del, results in the deletion of 1 amino acid(s) of the POLD1 protein (p.Glu279del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746341854, gnomAD 0.003%). This variant has been observed in individual(s) with breast and thyroid cancer (PMID: 34130653). ClinVar contains an entry for this variant (Variation ID: 484336). 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.
Counsyl	RCV000645839	SCV000784953	uncertain significance	Colorectal cancer, susceptibility to, 10	2017-02-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892024	SCV000806561	uncertain significance	POLD1-related condition	2024-01-12	criteria provided, single submitter	clinical testing	The POLD1 c.835_837delGAG variant is predicted to result in an in-frame deletion (p.Glu279del). This variant has been reported in one individual with a history of breast and thyroid cancer (Bakos et al. 2021. PubMed ID: 34130653). This variant is reported in 0.0020% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/484336/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679528	SCV000889694	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000679528	SCV001824710	uncertain significance	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000562268	SCV002534706	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469204	SCV002766200	uncertain significance	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.835_837delGAG (p.Glu279del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.3e-05 in 222876 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.835_837delGAG has been reported in the literature in at least one individual affected with Thyroid and Breast Cancer without evidence of causality (Bakos_2021). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.