NM_002691.4:c.1562G>A

POLD1 · NP_002682.2:p.(Arg521Gln) · NM_002691.4

GRCh37: chr19:50910307 G>A · GRCh38: chr19:50407050 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg521Gln)

gnomAD AF

0.0001611285942521712 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): gnomAD v4.1 allele frequency 0.016% (AF 0.000161) is below the 0.1% rare-variant threshold.

Overall classification: VUS - a single supporting-strength criterion satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination under the generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback: a single supporting-strength criterion (PM2) alone does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, so the variant is classified as Uncertain Significance.

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	Not applicable: missense substitution, so no null-variant mechanism such as nonsense-mediated decay or truncation applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no alternate nucleotide change producing p.Arg521Gln has been established as pathogenic; ClinVar shows only uncertain/conflicting submissions.	clinvar PMID:32792570
PS2	Not assessed	Not assessed: no parental genotypes or confirmed de novo occurrence was documented.	PMID:25741868
PS3	Not assessed	Not assessed: no validated functional assay directly testing p.Arg521Gln enzyme function was available.	PMID:32792570
PS4	Not assessed	Not assessed: no case-control enrichment or case-excess analysis for this exact variant was identified.	PMID:32792570
PM1	Not met	Not met: p.Arg521Gln lies outside the core Exo catalytic motifs, in a domain region where benign/uncertain missense variation is documented.	PMID:32792570
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 0.016% (AF 0.000161) is below the 0.1% rare-variant threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: no recessive POLD1 disease context or second pathogenic allele was identified.	PMID:25741868 PMID:26133394 PMID:32792570
PM4	N/A	Not applicable: missense substitution causes no protein-length change.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense at codon 521 established as pathogenic was identified.	pm5_candidates PMID:32792570
PM6	Not assessed	Not assessed: no de novo occurrence with unconfirmed parentage was documented.	PMID:25741868
PP1	Not assessed	Not assessed: no informative cosegregation data were available for this variant.	PMID:25741868 PMID:32792570
PP2	Not met	Not met: benign missense variation is not rare in the exonuclease domain; none of five surveyed outside-active-site missense variants reached pathogenic classification.	PMID:32792570 PMID:26133394
PP3	Not met	Not met: REVEL 0.278 falls in the gray zone (0.250-0.750), reaching neither the PP3 nor BP4 threshold.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: early-onset colorectal cancer alone is not a highly specific phenotype, and no POLD1-associated mutational signatures were present.	PMID:32792570
PP5	Not met	Not met: ClinVar has no expert-panel pathogenic or likely pathogenic assertion for this variant.	clinvar
BA1	Not met	Not met: highest population frequency (grpmax FAF 0.018%) is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: highest subgroup allele frequency 0.040% remains below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no observations in unaffected, appropriately aged individuals with phenotype information were available.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no validated functional assay result, benign or damaging, was available for this variant.	PMID:32792570
BS4	Not assessed	Not assessed: no informative lack of segregation was documented for this variant.	PMID:25741868 PMID:32792570
BP1	Not met	Not met: POLD1 cancer predisposition is caused predominantly by missense, not truncating, variants.	PMID:26133394 PMID:32792570
BP2	Not assessed	Not assessed: no observation of this variant in cis or trans with a pathogenic variant was available.	PMID:25741868
BP3	N/A	Not applicable: missense substitution is not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.278 is above the <0.25 BP4 threshold.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no independently established alternate molecular diagnosis explaining the phenotype was identified.	PMID:32792570
BP6	Not met	Not met: ClinVar has no expert-panel benign or likely benign assertion for this variant.	clinvar
BP7	N/A	Not applicable: missense substitution is not a synonymous variant, so the silent-variant premise does not apply.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.