POLD1 c.2388+5G>A, p.?
NM_002691.4:c.2388+5G>A
Variant of Uncertain Significance (VUS)
This intronic +5 splice region variant is extremely rare (PM2 Moderate) with no functional, segregation, or case data to support pathogenicity or benign impact. Insufficient evidence supports reclassification, thus the variant remains VUS.
ACMG/AMP Criteria Applied
PM2
Genetic Information
Gene & Transcript Details
Gene
POLD1
Transcript
NM_002691.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000019.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_002691.2 | Alternative | 27 exons | Forward |
| NM_002691.1 | Alternative | 27 exons | Forward |
| NM_002691.3 | Alternative | 27 exons | Forward |
Variant Details
HGVS Notation
NM_002691.4:c.2388+5G>A
Protein Change
?
Location
Exon 19
(Exon 19 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_002691.4
Genome Browser
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HGVS InputNM_002691:c.2388+5G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00574%
Rare
Highest in Population
Admixed American
0.0122%
Low Frequency
Global: 0.00574%
Admixed American: 0.0122%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 261350Alt: 15Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00574%, 15/261350 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.0122%, 4/32666 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This sequence change falls in intron 19 of the POLD1 gene. It does not directly change the encoded amino acid sequence of the POLD1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs750085275, gnomAD 0.01%). This variant has been observed in individual(s) with breast cancer (PMID: 34646395, 35534704). ClinVar contains an entry for this variant (Variation ID: 408012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). 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.
Variant summary: POLD1 c.2388+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical intron 19, 5' splicing donor site. However, these predictions have yet to be confirmed by peer reviewed functional studies. In-house RNA analysis demonstrated inconclusive levels of in-frame skipping of exon 19 resulting in r.2251_2388del (p.Val752_Val797del), however, the in-vivo relevance of this finding is unclear (internal data). To our knowledge, no pathogenic/likely pathogenic variants have been reported in exon 19. The variant allele was found at a frequency of 5.7e-05 in 229954 control chromosomes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome phenotype (6.3e-07) or susceptibility to colorectal cancer (1.4e-05). c.2388+5G>A has been reported in the literature as a VUS in settings of multigene panel testing for hereditary cancer but has not been reported in individuals with Autosomal Dominant Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome. The association of POLD1 with Autosomal Recessive Immunodeficiency 120 is limited at this moment and loss of function of POLD1 is not an established mechanism of disease. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with any of the POLD1-related disorders. 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: 34326862, 34646395, 35534704). ClinVar contains an entry for this variant (Variation ID: 408012). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The POLD1 2388+5G>A variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.45
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: NM_002691.4:c.2388+5G>A is a non‐canonical splice region variant at position +5, not a predicted LoF variant at canonical splice sites. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: it is intronic and does not result in an amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo or familial testing data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no data on occurrences in affected cohorts. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: it is intronic outside well-defined functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: MAF = 0.00574% in gnomAD (15/261,350 alleles), extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is at an extremely low frequency in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". The evidence for this variant shows: no information on phase with other variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: no in-frame indel or stop-loss effect. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: intronic splice region variant, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo evidence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: intronic variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational predictions are benign (CADD 2.45, low SpliceAI 0.27). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar reports VUS and likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF = 0.00574%, below the threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: frequency remains low, not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual with full penetrance expected at an early age". The evidence for this variant shows: no data on observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: intronic variant, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational predictions are benign but conflicting and not sufficient to apply. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case information. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar likely benign call has accessible evidence. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: intronic variant, not synonymous. Therefore, this criterion is not applied.