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
PALB2
Final classification
Benign
PALB2 c.2014G>C · p.Glu672Gln
PALB2
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
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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