rs2230243
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_002691.4(POLD1):c.1040C>T(p.Pro347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000697 in 1,563,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P347S) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1040C>T | p.Pro347Leu | missense_variant | 9/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1040C>T | p.Pro347Leu | missense_variant | 9/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000412 AC: 7AN: 169808Hom.: 0 AF XY: 0.0000443 AC XY: 4AN XY: 90390
GnomAD4 exome AF: 0.0000709 AC: 100AN: 1410790Hom.: 0 Cov.: 32 AF XY: 0.0000818 AC XY: 57AN XY: 697206
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2022 | Observed in individuals with colorectal cancer and/or endometrial cancer (Chubb et al., 2015; Hamzaoui et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 15766587, 29056344, 29120461, 32424176, 20951805) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 29, 2023 | In the published literature, this variant has been reported in individuals affected with an advanced adenoma (PMID: 33436027 (2021)), colorectal cancer (PMID: 25559809 (2015)), and in a woman affected with both colorectal cancer and endometrial cancer (PMID: 32424176 (2020)). The frequency of this variant in the general population, 0.000073 (5/68286 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2023 | The p.P347L variant (also known as c.1040C>T), located in coding exon 8 of the POLD1 gene, results from a C to T substitution at nucleotide position 1040. The proline at codon 347 is replaced by leucine, an amino acid with similar properties. This variant has been identified in CRC and adenoma cohorts (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32; Patel SG et al. Hered Cancer Clin Pract, 2021 Jan;19:8). This amino acid position is poorly 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. - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the POLD1 protein (p.Pro347Leu). This variant is present in population databases (rs2230243, gnomAD 0.008%). This missense change has been observed in individual(s) with rectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 408024). 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. - |
Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 02-15-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at