Starting

Initialising…

POLD1

Final classification

Likely Pathogenic

POLD1 c.2041del · p.Leu681SerfsTer13

POLD1

The POLD1 NM_002691.4:c.2041del (p.(Leu681SerfsTer13)) variant has been reported in ClinVar, where it is classified as uncertain significance by two clinical laboratories.

Gene

POLD1

Transcript

NM_002691.4

HGVS · transcript:coding

NM_002691.4:c.2041del

Consequence

N/A

GRCh38

chr19:50409548 AC>A

GRCh37

chr19:50912805 AC>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.

Classification rationale

PVS1PM2 Likely Pathogenic

POLD1 c.2041del

The POLD1 NM_002691.4:c.2041del (p.(Leu681SerfsTer13)) variant has been reported in ClinVar, where it is classified as uncertain significance by two clinical laboratories.¹ This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), which is well below the 0.1% rarity threshold used to support PM2.² No reviewed variant-specific functional studies were identified for this frameshift variant in the retrieved functional evidence sources.³ This is a truncating frameshift variant for which the generic PVS1 framework is applicable, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗spliceai ↗

Gene diagram · NM_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.1987e-07; MAF= 0.00006%, 1/1613242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47453e-07; MAF= 0.00008%, 1/1180006 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,242
0 hom

European (non-Finnish)

1 / 1,180,006

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots