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.1 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%.2 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.3
Final classification
Benign
BA1BP1BP6
PALB2
c.2014G>C
p.Glu672Gln
This variant
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.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP1 supporting, BP6 supporting benign; maps to Benign.
Classification rationale
BA1BP1BP6
Benign
PALB2 c.2014G>C
BA1 + BP1 + BP6
→
Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 8 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
BA1
stand-alone
Benign
This variant meets BA1. In gnomAD v4.1, the grpmax filtering allele frequency is 5.70171%, which is well above the PALB2 BA1 threshold of >0.1%; the highest observed population frequency is 15.35088% in the Amish population, and 715 homozygotes are present.
PALB2 BA1 threshold is grpmax filtering AF >0.1% in gnomAD v4Observed gnomAD v4 frequency is markedly above threshold
BP1
supporting
Benign
This variant meets BP1 because it is a missense substitution, and the PALB2 VCEP specification applies BP1 to all missense variants.
PALB2 VCEP instructs BP1 for all missense variants
Assessed · not applied
· 2 not met · 6 not assessed
Pathogenic
PVS1
This variant is a missense substitution, c.2014G>C (p.Glu672Gln; p.E672Q), and does not fall into the PALB2 loss-of-function variant categories used for PVS1.
PS4
Available evidence does not identify a qualifying case-control study for this exact variant showing a significant enrichment in affected individuals at the PALB2 VCEP threshold of p≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5.
PM2
This variant is far more common than the PALB2 PM2 threshold.
PM3
No data were identified showing this variant in trans with a pathogenic PALB2 variant in probands meeting the Fanconi anemia point-based PM3 framework.
PP1
No segregation data were identified that meet the PALB2 VCEP quantitative thresholds for PP1.
Benign
BS1
The population frequency also exceeds the PALB2 BS1 threshold of >0.01% in gnomAD v4.1, but BA1 is already met at a much higher frequency threshold, so BS1 was not additionally counted as separate benign evidence.
BS2
No qualifying PALB2 Fanconi anemia BS2 point-based data were identified.
BS4
No quantitative non-segregation data were identified that meet the PALB2 VCEP BS4 thresholds.
N/A · 17
PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
2.7%
· 43792 / 1,614,144
715 hom · FAF 5.7%
715 hom · FAF 5.7%
Amish 140 / 912 |
15% 12 hom |
Middle Eastern 377 / 6,062 |
6.2% 18 hom |
Ashkenazi Jewish 1093 / 29,600 |
3.7% 22 hom |
European (non-Finnish) 35343 / 1,180,024 |
3% 536 hom |
Remaining individuals 1708 / 62,502 |
2.7% 33 hom |
South Asian 2345 / 91,080 |
2.6% 70 hom |
European (Finnish) 1237 / 64,026 |
1.9% 10 hom |
Admixed American 1125 / 60,006 |
1.9% 12 hom |
African/African American 416 / 75,050 |
0.55% 2 hom |
East Asian 8 / 44,882 |
0.018% |
gnomAD v2.1
2.2%
· 6337 / 282,818
108 hom · FAF 2.8%
108 hom · FAF 2.8%
Ashkenazi Jewish 363 / 10,370 |
3.5% 4 hom |
European (non-Finnish) 3773 / 129,156 |
2.9% 70 hom |
Remaining individuals 197 / 7,220 |
2.7% 4 hom |
South Asian 813 / 30,616 |
2.7% 21 hom |
European (Finnish) 500 / 25,110 |
2% 2 hom |
Admixed American 553 / 35,434 |
1.6% 6 hom |
African/African American 136 / 24,960 |
0.54% 1 hom |
East Asian 2 / 19,952 |
0.01% |
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.736359.
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. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links