NM_002691.4:c.3305delC
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The NM_002691.4(POLD1):βc.3305delCβ(p.Pro1102LeufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,608,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Consequence
NM_002691.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3305delC | p.Pro1102LeufsTer22 | frameshift_variant | Exon 27 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3305delC | p.Pro1102LeufsTer22 | frameshift_variant | Exon 27 of 27 | 1 | NM_002691.4 | ENSP00000406046.1 | ||
ENSG00000142539 | ENST00000599632.1 | c.425+659delC | intron_variant | Intron 5 of 9 | 5 | ENSP00000473233.1 |
Frequencies
GnomAD3 genomes AF: 0.0000464 AC: 7AN: 150942Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000208 AC: 5AN: 240886Hom.: 0 AF XY: 0.00000763 AC XY: 1AN XY: 131074
GnomAD4 exome AF: 0.0000261 AC: 38AN: 1457798Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15AN XY: 724982
GnomAD4 genome AF: 0.0000464 AC: 7AN: 150942Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2AN XY: 73616
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: POLD1 c.3305delC (p.Pro1102LeufsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. c.3305delC (p.Pro1102LeufsX22) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.1e-05 in 240886 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3305delC in individuals affected with Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 408095). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
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Frameshift variant predicted to result in abnormal protein length as the last 6 amino acids are replaced with 21 different amino acids in a gene for which loss-of-function is not an established mechanism of disease; Observed in patients with pediatric leukemia, osteosarcoma, breast, or lung cancers (Lu et al., 2015; Alsultan et al., 2020; Mur et al., 2020; Zhang et al., 2015; Mirabello et al., 2020); This variant is associated with the following publications: (PMID: 32359129, 26689913, 32191290, 32792570, 26580448, 36451132) -
Colorectal cancer, susceptibility to, 10 Uncertain:2
This sequence change results in a frameshift in the POLD1 gene (p.Pro1102Leufs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the POLD1 protein and extend the protein by 15 additional amino acid residues. This variant is present in population databases (rs761614971, gnomAD 0.01%). This frameshift has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, and/or osteosarcoma (PMID: 32191290, 32359129, 32792570). ClinVar contains an entry for this variant (Variation ID: 408095). 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. -
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POLD1-related disorder Uncertain:1
The POLD1 c.3305delC variant is predicted to result in a frameshift and premature protein termination (p.Pro1102Leufs*22). This variant results in the last 6 amino acids being disrupted and extends the protein by 15 additional amino acids (p.Pro1102Leufs*22). This variant has been reported in individuals with lung squamous cell carcinoma, acute leukemia, and breast cancer (Supplementary data 2, Lu et al. 2015. PubMed ID: 26689913; Alsultan et al. 2020. PubMed ID: 32359129; Mur et al. 2020. PubMed ID: 32792570). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408095/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.3305delC variant, located in coding exon 26 of the POLD1 gene, results from a deletion of one nucleotide at nucleotide position 3305, causing a translational frameshift with a predicted alternate stop codon (p.P1102Lfs*22). This alteration occurs at the 3' terminus of thePOLD1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 15 amino acids. This frameshift impacts the last 6amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at