Submissions for variant NM_002691.4(POLD1):c.2327G>A (p.Arg776Gln)

gnomAD frequency: 0.00001  dbSNP: rs141801845

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230451	SCV000287567	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-12-23	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 776 of the POLD1 protein (p.Arg776Gln). This variant is present in population databases (rs141801845, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 239285). 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 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.
Baylor Genetics	RCV001292749	SCV001481391	uncertain significance	Mandibular hypoplasia-deafness-progeroid syndrome	2020-02-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001355034	SCV002571545	uncertain significance	not provided	2023-09-28	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 ovarian cancer (PMID: 30093976); This variant is associated with the following publications: (PMID: 20951805, 32041611, 30093976)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330596	SCV004037633	likely benign	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.2327G>A (p.Arg776Gln) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 248868 control chromosomes. The observed variant frequency is approximately 6.8 fold of 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 benign. c.2327G>A has been reported in the literature as a VUS in a cohort of individuals with 2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multigene panels (example, Chan_2018). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 32792570). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003330596	SCV004242998	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943794	SCV005476240	benign	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV005016634	SCV005650307	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-03-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355034	SCV001549794	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLD1 p.Arg776Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141801845) and ClinVar (classified as uncertain significance by Invitae for colorectal cancer). The variant was identified in control databases in 21 of 234444 chromosomes at a frequency of 0.00008957 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: South Asian in 17 of 30368 chromosomes (freq: 0.00056), Other in 2 of 5554 chromosomes (freq: 0.00036), Latino in 1 of 33916 chromosomes (freq: 0.000029) and European (non-Finnish) in 1 of 101812 chromosomes (freq: 0.00001), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg776 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.