Submissions for variant NM_002691.4(POLD1):c.2052G>C (p.Gln684His)

gnomAD frequency: 0.00045  dbSNP: rs144143245

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231655	SCV000287550	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000679487	SCV000568211	likely benign	not provided	2021-04-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28608266, 29212164, 26648538, 29987844, 31285513, 31449058, 32041611)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679487	SCV000601900	likely benign	not provided	2020-02-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564986	SCV000670883	benign	Hereditary cancer-predisposing syndrome	2024-02-28	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000679487	SCV000712639	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	The p.Gln684His variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 49/65572 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144143245). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln684His variant is uncertain.
Counsyl	RCV000231655	SCV000786056	uncertain significance	Colorectal cancer, susceptibility to, 10	2018-02-13	criteria provided, single submitter	clinical testing
Mendelics	RCV003492002	SCV000839443	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679487	SCV001152032	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	POLD1: BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679487	SCV002010604	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000485931	SCV002065993	uncertain significance	not specified	2017-10-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564986	SCV002534617	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000485931	SCV002551946	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000231655	SCV002580231	uncertain significance	Colorectal cancer, susceptibility to, 10	2022-04-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000231655	SCV003843084	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-09-22	criteria provided, single submitter	clinical testing	The POLD1 c.2052G>C (p.Gln684His) missense change has a maximum subpopulation frequency of 0.088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colon cancer and/or colon polyposis (PMID: 29987844, 31285513, 29212164). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000231655	SCV000493785	uncertain significance	Colorectal cancer, susceptibility to, 10	2016-01-27	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000564986	SCV000805288	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529392	SCV000806486	uncertain significance	POLD1-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The POLD1 c.2052G>C variant is predicted to result in the amino acid substitution p.Gln684His. This variant has been reported in multiple individuals in the literature, such as: an individual with microsatellite stable colorectal cancer (Raskin et al. 2017. PubMed ID: 29212164), an individual with clinically suspected Lynch syndrome and loss of MSH2 in tumor tissue (the individual harbored additional variants; Kayser et al. 2018. PubMed ID: 29987844, Table S6, Patient 25), an individual with breast cancer (the individual harbored additional variants; Dominguez-Valentin et al. 2018. PubMed ID: 28608266, Table 2), an individual with attenuated adenomatous polyposis (Lorca et al. 2019. PubMed ID: 31285513, Table 2), and an individual with multiple primary cancer, who also carried several variants in other genes (Sylvester. 2021. PubMed ID: 34687117, patient MO111041 in Table S4 and Table S5). This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239269/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000231655	SCV000844938	uncertain significance	Colorectal cancer, susceptibility to, 10	2018-06-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679487	SCV001551471	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLD1 p.Gln684His variant was identified in 1 of 2092 proband chromosomes (frequency: 0.0005) from individuals or families with colon cancer (Raskin 2017). The variant was also identified in dbSNP (ID: rs144143245) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and six clinical laboratories), MutDB, and in LOVD 3.0 (1x). The variant was not identified in Cosmic database. The variant was identified in control databases in 120 of 276056 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23958 chromosomes (freq: 0.00008), Other in 1 of 6448 chromosomes (freq: 0.0002), Latino in 11 of 34410 chromosomes (freq: 0.0003), European in 79 of 125698 chromosomes (freq: 0.0006), Ashkenazi Jewish in 4 of 10132 chromosomes (freq: 0.0004), Finnish in 23 of 25792 chromosomes (freq: 0.0009); it was not observed in the East Asian and South Asian populations. The p.Gln684 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679487	SCV001808865	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679487	SCV001919325	likely benign	not provided		no assertion criteria provided	clinical testing