Submissions for variant NM_002691.4(POLD1):c.841-10A>G

gnomAD frequency: 0.00003  dbSNP: rs140160345

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759969	SCV000528087	likely benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV001082324	SCV000558764	likely benign	Colorectal cancer, susceptibility to, 10	2024-01-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759969	SCV000889696	likely benign	not provided	2017-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000444281	SCV000918079	benign	not specified	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.841-10A>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. 4/4 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 6.3e-05 in 175902 control chromosomes. The observed variant frequency is approximately 4.4 fold above 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 benign. To our knowledge, no occurrence of c.841-10A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000444281	SCV002551890	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354233	SCV001548795	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 c.841-10A>G variant was not identified in the literature nor was it identified in the Cosmic or Clinvitae database. The variant was also identified in dbSNP (ID: rs140160345) as “With Likely benign allele”, ClinVar (classified as likely benign by GeneDx and Invitae; as uncertain significance by Quest Diagnostics Nichols Institute San Juan Capistrano), and LOVD 3.0 (1x) databases. The variant was identified in control databases in 11 of 175902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 4280 chromosomes (freq: 0.0002), Latino in 1 of 25734 chromosomes (freq: 0.00004), European in 9 of 73424 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.