Submissions for variant NM_002691.4(POLD1):c.2103C>T (p.Tyr701=)

gnomAD frequency: 0.00046  dbSNP: rs201483538

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079593	SCV000287553	benign	Colorectal cancer, susceptibility to, 10	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000434365	SCV000519115	likely benign	not specified	2017-09-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679489	SCV000601905	benign	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575474	SCV000670945	likely benign	Hereditary cancer-predisposing syndrome	2015-07-21	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	RCV000679489	SCV000806490	likely benign	not provided	2017-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000434365	SCV000918080	benign	not specified	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.2103C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.00085 in 119288 control chromosomes in the ExAC database, including 1 homozygote. The observed variant frequency is approximately 60 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 benign. To our knowledge, no occurrence of c.2103C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000679489	SCV001152033	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000434365	SCV002065994	likely benign	not specified	2018-11-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575474	SCV002534620	likely benign	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000434365	SCV002551948	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079593	SCV004016650	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000575474	SCV000788136	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356425	SCV001551589	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Tyr701= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in the following databases: dbSNP (ID: rs201483538) as “With Likely benign allele “, ClinVar and Clinvitae (4x as benign by Invitae, and as likely benign by GeneDx, Quest Diagnostics and Ambry Genetics). The variant was identified in control databases in 195 of 276096 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 2 of 23960 chromosomes (freq: 0.00008), “Other” in 2 of 6448 chromosomes (freq: 0.0003), Latino in 6 of 34352 chromosomes (freq: 0.0002), European Non-Finnish in 76 of 125882 chromosomes (freq: 0.0006), European Finnish in 6 of 25776 chromosomes (freq: 0.0002), and South Asian in 103 of 30756 chromosomes (freq: 0.003). While the variant was not observed in the Ashkenazi Jewish or East Asian populations. The p.Tyr701= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.