rs780138978
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002691.4(POLD1):c.2326C>T(p.Arg776Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,612,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2326C>T | p.Arg776Trp | missense_variant | Exon 19 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000763 AC: 19AN: 248910Hom.: 0 AF XY: 0.0000668 AC XY: 9AN XY: 134630
GnomAD4 exome AF: 0.0000596 AC: 87AN: 1459780Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48AN XY: 726198
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74374
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.R776W variant (also known as c.2326C>T), located in coding exon 18 of the POLD1 gene, results from a C to T substitution at nucleotide position 2326. The arginine at codon 776 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
not specified Uncertain:1Benign:1
Variant summary: POLD1 c.2326C>T (p.Arg776Trp) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 248910 control chromosomes. The observed variant frequency is approximately 5.37 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. c.2326C>T has been reported in the literature in individuals control individual(s) (Arora_2015) and in breast tumor tissue (Doisy_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
The p.Arg776Trp variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 1/6594 of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs780138978). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg776Trp variant is uncertain. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a control individual reporting no personal or family history of colorectal cancer (PMID: 26344056); This variant is associated with the following publications: (PMID: 29917049, 31422818, 20951805, 26344056) -
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 776 of the POLD1 protein (p.Arg776Trp). This variant is present in population databases (rs780138978, 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: 239284). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at