NM_002691.4:c.2915C>T

POLD1 · NP_002682.2:p.(Pro972Leu) · NM_002691.4

GRCh37: chr19:50919747 C>T · GRCh38: chr19:50416490 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Pro972Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLD1 c.2915C>T (p.Pro972Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.

This variant is absent from gnomAD v2.1 and has 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity.

Cancer Hotspots did not identify residue Pro972 as a statistically significant hotspot, which does not support application of PM1.

Available computational evidence does not support a damaging or splice-altering effect, with REVEL 0.274, BayesDel -0.220831, and SpliceAI maximum delta score 0.01.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, NM_002691.4:c.2915C>T (p.Pro972Leu), and it does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although gene-level review supports that loss of function can be a disease mechanism in POLD1, the generic PVS1 scaffold does not support applying PVS1 to this amino acid substitution.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this same amino acid change, p.Pro972Leu, has already been established as pathogenic through a different nucleotide change.	clinvar
PS2	Not met	No confirmed de novo occurrence with established maternity and paternity was identified for this variant.	clinvar
PS3	Not met	No well-established functional study for this exact variant was identified demonstrating a damaging effect on POLD1 function.	oncokb PMID:28492532
PS4	Not met	This variant has not been shown to be significantly enriched in affected individuals compared with controls. Current evidence shows one ClinVar submission and no case-control enrichment data.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available hotspot evidence does not support that residue Pro972 lies in a well-established mutational hotspot or critical region without benign variation. Cancer Hotspots did not identify this residue as a statistically significant hotspot.	hotspots oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and observed at 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity in non-VCEP review. These data support that the variant is rare in population databases.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder context.
PM4	N/A	This criterion applies to protein length changes from in-frame insertions/deletions or stop-loss variants, and this variant is a missense substitution.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at codon 972 that would support PM5.	clinvar
PM6	Not met	No assumed de novo occurrence without confirmation of maternity and paternity was identified for this variant.	clinvar
PP1	Not met	No segregation data were identified showing that this variant tracks with disease in affected relatives.	clinvar
PP2	Not assessed	Available evidence for this case does not establish that POLD1 is a gene in which missense variation is a sufficiently common and well-supported disease mechanism to apply PP2 for this variant alone.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a deleterious effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact.	revel bayesdel spliceai
PP4	Not assessed	No phenotype or family-history information was provided that is highly specific for a single genetic etiology and attributable to this variant.
PP5	Not assessed	No reputable-source pathogenic assertion was used without access to the underlying evidence. The available ClinVar record is a single-submitter VUS and does not support PP5.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. gnomAD v4.1 shows 0/1,552,088 alleles (0.00000%), which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency does not meet the benign strong threshold. gnomAD v4.1 shows 0/1,552,088 alleles (0.00000%), which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	This variant was not observed in population databases in a manner that would support occurrence in healthy adults at a frequency expected for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional study for this exact variant was identified showing normal POLD1 function.	oncokb PMID:28492532
BS4	Not met	No non-segregation data were identified showing that this variant fails to track with disease in a family.	clinvar
BP1	Not assessed	Available evidence does not establish that POLD1 is a gene in which truncating variants are the primary disease mechanism such that a missense variant would favor BP1.	pvs1_gene_context
BP2	Not assessed	No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.
BP3	N/A	This criterion applies to in-frame indels in repetitive regions without known function, and this variant is a missense substitution.
BP4	Met	Multiple computational results do not support a damaging or splice-altering effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis or other clearly explanatory variant data were provided to support BP5.
BP6	Not assessed	No reputable-source benign assertion was used without access to the underlying evidence. The available ClinVar record is a single-submitter VUS and does not support BP6.	clinvar
BP7	N/A	This criterion applies to synonymous variants with no predicted splice impact, and this variant is a missense substitution.

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