Submissions for variant NM_002691.4(POLD1):c.1433G>A (p.Ser478Asn)

dbSNP: rs397514632

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000033142	SCV000488513	likely pathogenic	Colorectal cancer, susceptibility to, 10	2016-06-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033142	SCV000646484	pathogenic	Colorectal cancer, susceptibility to, 10	2024-02-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 478 of the POLD1 protein (p.Ser478Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer, endometrial cancer and astrocytoma (PMID: 23263490, 25559809, 26344056). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40044). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects POLD1 function (PMID: 23263490). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000033142	SCV004018540	likely pathogenic	Colorectal cancer, susceptibility to, 10	2023-04-19	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23263490]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV000033142	SCV004203488	pathogenic	Colorectal cancer, susceptibility to, 10	2023-07-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943734	SCV005476302	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-06	criteria provided, single submitter	clinical testing	The p.S478N variant (also known as c.1433G>A), located in coding exon 11 of the POLD1 gene, results from a G to A substitution at nucleotide position 1433. The serine at codon 478 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with POLD1-related polymerase proofreading-associated polyposis. In addition, this variant was reported to segregate with disease in multiple families (Palles C et al. Nat Genet, 2013 Feb;45:136-44; Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32; Arora S et al. Gastroenterology, 2015 Dec;149:1872-1883.e9; Jansen AML et al. Fam Cancer, 2020 Jan;19:1-10; Ito T et al. Jpn J Clin Oncol, 2020 Sep;50:1080-1083). In multiple assays testing POLD1 function, this variant showed functionally abnormal results (Palles C et al. Nat Genet, 2013 Feb;45:136-44; Oh DY et al. Hum Mutat, 2020 May;41:913-920). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000033142	SCV000056924	risk factor	Colorectal cancer, susceptibility to, 10	2015-08-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358647	SCV001554442	pathogenic	not provided		no assertion criteria provided	clinical testing	The POLD1 p.Ser478Asn variant was identified in 2 of 1302 proband chromosomes (frequency: 0.002) from individuals or families with colorectal cancer (Arora 2015, Chubb 2015). The variant was also identified in dbSNP (ID: rs397514632) as “With other allele”, ClinVar (classified as pathogenic by Invitae, likely pathogenic by Counsyl, and as a risk factor by OMIM). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser478 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. However, this variant is located in the exonuclease domain of the enzyme and is suggested to affect the secondary structure of this active site (Briggs 2013, Palles 2013). The variant has also been reported to segregate with disease in several affected individuals in at least two unrelated families (Briggs 2013, Palles 2013). A functional study in yeast demonstrated that this variant resulted in a 12-fold increase in mutation rate as compared to wild type (Palles 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 pathogenic.