Submissions for variant NM_002691.4(POLD1):c.2017G>A (p.Glu673Lys)

gnomAD frequency: 0.00018  dbSNP: rs61751955

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203677	SCV000261910	likely benign	Colorectal cancer, susceptibility to, 10	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000236689	SCV000293993	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with personal and/or family history of cancer (PMID: 35534704); This variant is associated with the following publications: (PMID: 20951805, 33111339, 35534704)
Ambry Genetics	RCV000564370	SCV000670920	likely benign	Hereditary cancer-predisposing syndrome	2024-08-20	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.
PreventionGenetics, part of Exact Sciences	RCV000236689	SCV000806485	uncertain significance	not provided	2017-08-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236689	SCV001134634	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236689	SCV002010606	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818504	SCV002066949	uncertain significance	not specified	2019-02-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818504	SCV004242996	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025334	SCV005650304	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818504	SCV005726085	likely benign	not specified	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.2017G>A (p.Glu673Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249714 control chromosomes. The observed variant frequency is approximately 10.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05). c.2017G>A has been reported in the literature in the heterozygous state in at least 1 individual affected with ovarian cancer (example, Mur_2020). These report(s) do not provide unequivocal conclusions about association of the variant with POLD1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32792570). ClinVar contains an entry for this variant (Variation ID: 220938). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236689	SCV001548911	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLD1 p.Glu673Lys variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, MutDB or Insight Hereditary Tumors Database,. The variant was identified in dbSNP (ID: rs61751955) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae and GeneDx), Clinvitae (2x), and in control databases in 41 of 275668 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6442 chromosomes (freq: 0.0003), Latino in 7 of 34418 chromosomes (freq: 0.0002), European Non-Finnish in 31 of 125274 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10142 chromosomes (freq: 0.0001), while not observed in the African, East Asian, European Finnish and South Asian populations. The p.Glu673Lys variant falls within the DNA-directed DNA polymerase, family B functional domain and therefore may have clinical importance. The p.Glu673 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Lys to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.