19-50407061-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002691.4(POLD1):c.1573C>T(p.Arg525Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R525Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1573C>T | p.Arg525Trp | missense_variant | 13/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1573C>T | p.Arg525Trp | missense_variant | 13/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250710Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135606
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461452Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727062
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152300Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 4AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of breast and colorectal cancer, who also harbored a pathogenic variant in ATM (Mur et al., 2020); This variant is associated with the following publications: (PMID: 27913435, 35620275, 20951805, 32792570, 31422818) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 31, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 27, 2017 | The p.Arg525Trp variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been identified in 3/10312 of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs201804732). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Arg525Trp variant is uncertain. - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 525 of the POLD1 protein (p.Arg525Trp). This variant is present in population databases (rs201804732, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 469206). 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 not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2022 | The p.R525W variant (also known as c.1573C>T), located in coding exon 12 of the POLD1 gene, results from a C to T substitution at nucleotide position 1573. The arginine at codon 525 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in 1/2813 unrelated individuals undergoing multigene panel testing for hereditary cancer (Mur P et al. Genet. Med., 2020 Aug). This variant was also detected in a study of 1165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at