19-50398897-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002691.4(POLD1):c.46A>G(p.Lys16Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000293 in 1,604,258 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. K16T) 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.46A>G | p.Lys16Glu | missense_variant | 2/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.46A>G | p.Lys16Glu | missense_variant | 2/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000388 AC: 9AN: 232016Hom.: 0 AF XY: 0.0000637 AC XY: 8AN XY: 125598
GnomAD4 exome AF: 0.0000296 AC: 43AN: 1451902Hom.: 0 Cov.: 33 AF XY: 0.0000444 AC XY: 32AN XY: 721372
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74504
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Oct 01, 2016 | Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 43 year old female with a history of 1 colon polyp and family history of colon cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer who also harbored a pathogenic BRCA2 variant (Borazanci et al., 2020); This variant is associated with the following publications: (PMID: Botrus2022[article], 31391296) - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 16 of the POLD1 protein (p.Lys16Glu). This variant is present in population databases (rs765185645, gnomAD 0.02%). 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: 496661). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 p.Lys16Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs765185645) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae and University of Washington). The variant was identified in control databases in 11 of 258,648 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 117,476 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9552 chromosomes (freq: 0.0001), East Asian in 1 of 18,040 chromosomes (freq: 0.00006) and South Asian in 6 of 28,810 chromosomes (freq: 0.0002). The variant was not observed in the African, Other, Latino and Finnish populations. The p.Lys16 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at