ClinVar Miner

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

gnomAD frequency: 0.00013  dbSNP: rs199993010
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Total submissions: 10
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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

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