Submissions for variant NM_002691.4(POLD1):c.1138-8A>G

gnomAD frequency: 0.00056  dbSNP: rs41544624

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204543	SCV000261553	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000204543	SCV000489308	likely benign	Colorectal cancer, susceptibility to, 10	2016-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000679473	SCV000521703	likely benign	not provided	2021-10-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28577310, 28423643)
PreventionGenetics, part of Exact Sciences	RCV000679473	SCV000806458	likely benign	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679473	SCV000888430	benign	not provided	2022-09-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000204543	SCV001141140	likely benign	Colorectal cancer, susceptibility to, 10	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437496	SCV001370705	benign	not specified	2020-05-07	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.1138-8A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00061 in 251010 control chromosomes, predominantly at a frequency of 0.0016 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 113 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000664280	SCV002529047	benign	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000437496	SCV002551904	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679473	SCV003918170	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	POLD1: BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204543	SCV004016635	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204543	SCV004018511	likely benign	Colorectal cancer, susceptibility to, 10	2023-04-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000204543	SCV000733913	likely benign	Colorectal cancer, susceptibility to, 10		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000664280	SCV000788124	likely benign	Hereditary cancer-predisposing syndrome	2018-01-24	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679473	SCV001808528	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679473	SCV001919141	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679473	SCV001951919	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679473	SCV001971753	likely benign	not provided		no assertion criteria provided	clinical testing