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

gnomAD frequency: 0.00110  dbSNP: rs145473716

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206687	SCV000262152	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	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	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.
PreventionGenetics, part of Exact Sciences	RCV004529002	SCV000806496	benign	POLD1-related disorder	2019-08-26	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLD1: BS2
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000217194	SCV002551959	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679493	SCV003800462	benign	not provided	2022-04-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206687	SCV004018536	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.
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.