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LYFE SCIENCES
Project: HERA
NM_024675.3:c.2014G>C
p.Glu672Gln  ·  PALB2
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Classification rationale
1

The PALB2 c.2014G>C (p.Glu672Gln; p.E672Q) variant has been reported in ClinVar as Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, with additional benign and likely benign clinical laboratory submissions.

clinvar ↗
2

This variant is common in population databases; in gnomAD v4.1 the allele frequency is 2.71302% with a grpmax filtering allele frequency of 5.70171%, and the highest observed population frequency is 15.35088% in the Amish population, which is well above the PALB2 BA1 threshold of 0.1%.

gnomad_v4 ↗ cspec ↗
3

Computational data do not support a deleterious effect: SpliceAI predicts no significant splice impact with a max delta score of 0.01, REVEL is 0.029, and BayesDel is -0.736359; however, the PALB2 VCEP specification does not apply PP3 or BP4 to missense variants.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 0.0224066; MAF= 2.24066%, 6337/282818 alleles, homozygotes = 108) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0350048; MAF= 3.50048%, 363/10370 alleles, homozygotes = 4); grpmax FAF= 0.0284581.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.0271302; MAF= 2.71302%, 43792/1614144 alleles, homozygotes = 715) and has highest observed frequency in the Amish population (AF= 0.153509; MAF= 15.35088%, 140/912 alleles, homozygotes = 12); grpmax FAF= 0.0570171.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (22 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.736359.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55161919, n = 30 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE672
Hotspots ↗