Submissions for variant NM_002691.4(POLD1):c.961G>A (p.Gly321Ser)

gnomAD frequency: 0.00029  dbSNP: rs41554817

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204540	SCV000262340	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000204540	SCV000489570	uncertain significance	Colorectal cancer, susceptibility to, 10	2016-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000657083	SCV000568613	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30827058, 30680046, 20951805, 25938944, 27320729, 26648449, 28188185, 29120461, 33193653, 33332384, 34326862, 35264596, 37088804)
Ambry Genetics	RCV000564226	SCV000670900	likely benign	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Mendelics	RCV000709584	SCV000839440	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657083	SCV000889703	uncertain significance	not provided	2022-12-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00066 (82/124328 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with colorectal polyps and colorectal cancer (PMIDs: 26648449 (2015), 25938944 (2015), 30827058 (2018), and 33193653 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764216	SCV000895219	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657083	SCV001152021	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000204540	SCV001775525	uncertain significance	Colorectal cancer, susceptibility to, 10	2021-08-05	criteria provided, single submitter	clinical testing	The POLD1 c.961G>A (p.Gly321Ser) missense change has a maximum subpopulation frequency of 0.066% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/19-50905989-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in the literature in individuals with a personal and/or family history of colorectal cancer (PS4_supporting; PMID: 26648449, 30827058, 33193653), in an individual with colon polyps (PMID: 25938944), in an individual with multiple endocrine neoplasia, type II (PMID: 30680046), and in non-cancer controls (PMID: 30267214). One individual with >100 colorectal polyps and colorectal cancer diagnosed at age 37 also carried a heterozygous pathogenic variant in MUTYH (PMID: 30827058). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS4_supporting.
Sema4, Sema4	RCV000564226	SCV002534716	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267945	SCV002551895	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204540	SCV004018516	uncertain significance	Colorectal cancer, susceptibility to, 10	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657083	SCV004225433	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927883	SCV004739002	uncertain significance	POLD1-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The POLD1 c.961G>A variant is predicted to result in the amino acid substitution p.Gly321Ser. This variant has been reported in an individual with adenomatous polyps and a family history of colorectal cancer or adenomatous polyposis (Weren et al. 2015. PubMed ID: 25938944) and an individual suspected of having Lynch syndrome (Jansen et al. 2016. PubMed ID: 26648449). Two additional unrelated patients with multiple colorectal polyps and colorectal cancer were also reported to have this variant; the variant did not co-segregate with disease in one family and co-segregation analysis was unavailable for the other family (Table 2 and Figure 1A, Elsayed et al. 2019. PubMed ID: 30827058). It was also reported as a variant of uncertain significance in a study of individuals with early-onset colorectal cancer or familial colorectal cancer (Djursby et al. 2020. PubMed ID: 33193653) and in a study of patients with a suspected hereditary tumor syndrome (Henn et al. 2019. PubMed ID: 30680046). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as both a variant of uncertain significance and likely benign in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/221136/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
True Health Diagnostics	RCV000564226	SCV000788156	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356862	SCV001552136	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Gly321Ser variant was identified in 5 of 1364 proband chromosomes (frequency: 0.004) from individuals with colorectal and medullary thyroid cancer (Weren 2015, Jansen 2016, Elsayed 2019, Henn 2019). The variant was identified in dbSNP (rs41554817) as “with uncertain significance allele”, ClinVar (interpreted as uncertain significance by Invitae, Ambry Genetics and 7 others). The variant was identified in control databases in 88 of 268,044 chromosomes at a frequency of 0.000328 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 3 of 23418 chromosomes (freq: 0.0001), Other in 1 of 6224 chromosomes (freq: 0.0002), Latino in 7 of 33,760 chromosomes (freq: 0.0002), European in 75 of 122,102 chromosomes (freq: 0.0006), Finnish in 1 of 24,360 chromosomes (freq: 0.00004), and South Asian in 1 of 29,884 chromosomes (freq: 0.00003). The variant was not observed in the Ashkenazi Jewish and East Asian populations. The variant affects the exonuclease domain of POLD1, but functional analysis would be needed to determine if there is a deleterious effect on the protein. The p.Gly321 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657083	SCV001742598	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000657083	SCV001807490	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000657083	SCV001925623	uncertain significance	not provided		no assertion criteria provided	clinical testing