rs141801845
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_002691.4(POLD1):c.2327G>A(p.Arg776Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,612,274 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2327G>A | p.Arg776Gln | missense_variant | Exon 19 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152262Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000964 AC: 24AN: 248868Hom.: 0 AF XY: 0.0000594 AC XY: 8AN XY: 134654
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1459894Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27AN XY: 726268
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152380Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74518
ClinVar
Submissions by phenotype
not provided Uncertain:2
The POLD1 p.Arg776Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141801845) and ClinVar (classified as uncertain significance by Invitae for colorectal cancer). The variant was identified in control databases in 21 of 234444 chromosomes at a frequency of 0.00008957 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: South Asian in 17 of 30368 chromosomes (freq: 0.00056), Other in 2 of 5554 chromosomes (freq: 0.00036), Latino in 1 of 33916 chromosomes (freq: 0.000029) and European (non-Finnish) in 1 of 101812 chromosomes (freq: 0.00001), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg776 residue is conserved 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 three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not 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. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with ovarian cancer (PMID: 30093976); This variant is associated with the following publications: (PMID: 20951805, 32041611, 30093976) -
not specified Uncertain:1Benign:1
Variant summary: POLD1 c.2327G>A (p.Arg776Gln) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 248868 control chromosomes. The observed variant frequency is approximately 6.8 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.2327G>A has been reported in the literature as a VUS in a cohort of individuals with 2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multigene panels (example, Chan_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. The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 32792570). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
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Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 776 of the POLD1 protein (p.Arg776Gln). This variant is present in population databases (rs141801845, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 239285). 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. -
Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 Uncertain:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at