ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2275G>A (p.Val759Ile)

gnomAD frequency: 0.00110  dbSNP: rs145473716
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206687 SCV000262152 benign Colorectal cancer, susceptibility to, 10 2021-11-30 criteria provided, single submitter clinical testing
Vantari Genetics RCV000210771 SCV000267079 likely benign Hereditary cancer-predisposing syndrome 2015-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000679493 SCV000279378 benign not provided 2019-07-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25986922, 25822476, 23376243, 27153395, 30086056)
Counsyl RCV000206687 SCV000488800 uncertain significance Colorectal cancer, susceptibility to, 10 2016-07-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000217194 SCV000540078 likely benign not specified 2016-12-02 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.242% (35 South Asian and 150 European alleles) and 2% in gnomAD (207 Ashkenazi alleles - too high for disease prevalence). It is classified in ClinVar with 1 star as Likely benign by 2 submitters (Invitae, Vantari) and as VUS by GeneDx.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217194 SCV000601913 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210771 SCV000670921 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
PreventionGenetics,PreventionGenetics RCV000679493 SCV000806496 likely benign not provided 2017-01-13 criteria provided, single submitter clinical testing
Mendelics RCV000206687 SCV001141154 likely benign Colorectal cancer, susceptibility to, 10 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000679493 SCV001152035 uncertain significance not provided 2016-05-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000217194 SCV002065996 benign not specified 2018-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217194 SCV002103675 likely benign not specified 2022-02-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000210771 SCV002534627 benign Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter curation
True Health Diagnostics RCV000210771 SCV000788138 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001269368 SCV001448705 benign Malignant tumor of breast no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000217194 SCV001551682 benign not specified no assertion criteria provided clinical testing The POLD1 p.Val759Ile variant was identified in 4 of 84 proband chromosomes (frequency: 0.0476) from individuals or families with early-onset colon cancer (Rosner_2015). The variant was also identified in dbSNP (ID: rs145473716) as “With other allele”, ClinVar (as benign by Invitae, as likely benign by Vantari Genetics, GeneDx, Partners Health Care Personalized Medicine, Quest Diagnostics, and Ambry Genetics, and as uncertain significance by Counsyl), Clinvitae (3x), and Cosmic (in somatic tumours in the large intestine and central nervous system). The variant was not identified in the MutDB database. The variant was identified in control databases in 461 of 273426 chromosomes (8 homozygous) at a frequency of 0.001686 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24014 chromosomes (freq: 0.000042), Other in 12 of 6404 chromosomes (freq: 0.001874), Latino in 21 of 34128 chromosomes (freq: 0.000615), European (Non-Finnish) in 116 of 125376 chromosomes (freq: 0.000925), Ashkenazi Jewish in 209 of 9996 chromosomes (freq: 0.02091), East Asian in 19 of 18792 chromosomes (freq: 0.001011), and South Asian in 83 of 30524 chromosomes (freq: 0.002719), while the variant was not observed in the European (Finnish) populations. Interestingly, in a study of genetic variants that cause longevity, the p.Val759Ile variant was found in 14 controls and 17 centenarians (individuals over 105 years old) (Han_2013_23376243). The p.Val759 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000217194 SCV002551959 uncertain significance not specified 2022-01-04 no assertion criteria provided clinical testing

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