Variant classification summary

NM_002691.4:c.653G>A

POLD1 · NP_002682.2:p.(Arg218His) · NM_002691.4

GRCh37: chr19:50905525 G>A · GRCh38: chr19:50402268 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg218His)

gnomAD AF

0.0004872298428901826 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): Ashkenazi Jewish allele frequency 0.5135% in gnomAD v4.1 exceeds the 0.3% BS1 benign threshold.

2

BP4 (Supporting): REVEL score 0.19 is below the <=0.290 benign computational threshold.

3

Final: BS1 (strong) plus BP4 (supporting) with no met pathogenic criterion maps to Likely Benign under generic ACMG/AMP combining rules.

Final determination: Generic ACMG/AMP 2015 fallback: one strong benign criterion (BS1) plus one supporting benign criterion (BP4), with no pathogenic evidence met, combines to Likely Benign.

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 p.(Arg218His) does not trigger any null-variant mechanism such as nonsense-mediated decay or truncation.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available.
PS2	Not assessed	Not assessed: no de novo occurrence or parental genotype data were available for the proband.	PMID:25741868
PS3	Not assessed	Not assessed: no functional assay data on p.Arg218His polymerase or proofreading activity were available.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this exact variant were available.	clinvar
PM1	Not assessed	Not assessed: insufficient evidence was available.
PM2	Not met	Not met: allele frequency 0.5135% in Ashkenazi Jewish gnomAD v4.1 exceeds the 0.3% BS1 threshold, so the variant is not rare.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual with this variant in trans with a pathogenic POLD1 variant was observed.	generic_acmg_combination_rules PMID:25741868
PM4	N/A	Not applicable: missense substitution causes no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available.
PM6	Not assessed	Not assessed: no de novo observation or parental testing data were available.	PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or co-segregation data were available.	PMID:25741868
PP2	Not assessed	Not assessed: insufficient evidence was available.
PP3	Not met	Not met: REVEL score 0.19 is far below the >=0.644 PP3 supporting threshold.	revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specific testing context was provided.	clinvar
PP5	Not met	Not met: the ClinVar record has no expert-panel pathogenic or likely pathogenic classification.	clinvar
BA1	Not met	Not met: highest population allele frequency 0.5216% is well below the 5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Met (strong): Ashkenazi Jewish frequency 0.5135% in gnomAD v4.1 exceeds the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD v4.1 homozygotes lack phenotype and penetrance data needed for this cancer-predisposition context.	gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal activity for p.Arg218His were available.
BS4	Not assessed	Not assessed: no family genotype-phenotype or non-segregation data were available.	PMID:25741868
BP1	Not assessed	Not assessed: insufficient evidence was available.
BP2	Not assessed	Not assessed: no observation of this variant with a pathogenic POLD1 variant in cis or trans was available.	generic_acmg_combination_rules PMID:25741868
BP3	N/A	Not applicable: applies only to in-frame indels in repetitive regions; this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.19 is below the <=0.290 BP4 supporting threshold.	revel spliceai
BP5	Not assessed	Not assessed: no evidence that the phenotype is explained by an alternative molecular diagnosis was available.	clinvar
BP6	Not met	Not met: the ClinVar record has no expert-panel benign or likely benign classification.	clinvar
BP7	N/A	Not applicable: applies only to synonymous variants; this is a missense substitution.	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.