Submissions for variant NM_002691.4(POLD1):c.371T>C (p.Val124Ala)

gnomAD frequency: 0.00013  dbSNP: rs199993010

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080725	SCV000261978	likely benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657084	SCV000568650	uncertain significance	not provided	2017-12-04	criteria provided, single submitter	clinical testing	This variant is denoted POLD1 c.371T>C at the cDNA level, p.Val124Ala (V124A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a lung tumor (Jiang 2016). POLD1 Val124Ala was observed at an allele frequency of 0.3% (56/18,862) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether POLD1 Val124Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657084	SCV000601941	benign	not provided	2018-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561011	SCV000670951	likely benign	Hereditary cancer-predisposing syndrome	2015-06-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778795	SCV002014993	likely benign	not specified	2021-10-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001778795	SCV004026981	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530245	SCV004742083	likely benign	POLD1-related disorder	2019-05-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356860	SCV001552133	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Val124Ala variant was not identified in the literature. The variant was identified in dbSNP (ID: rs199993010) as "With other allele", and in ClinVar (classified as likely benign by Invitae, Ambry Genetics and one clinical laboratory; as uncertain significance by GeneDx).The variant was identified in control databases in 63 of 276530 chromosomes at a frequency of 0.0002 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 1 of 23974 chromosomes (freq: 0.00004), East Asian in 56 of 18862 chromosomes (freq: 0.003), and South Asian in 6 of 30780 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, and Finnish populations. The p.Val124 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
Clinical Genetics, Academic Medical Center	RCV000657084	SCV001926205	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000657084	SCV001974996	likely benign	not provided		no assertion criteria provided	clinical testing