The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.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% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.2 This variant introduces a premature stop codon early in PALB2, and published PALB2 studies together with the PALB2 specification support loss of function as an established disease mechanism for hereditary cancer predisposition.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which does not support PP3 and is consistent with the primary consequence being protein truncation rather than altered splicing.4
PALB2
Final classification
Pathogenic
PALB2 c.682C>T · p.Gln228Ter
PALB2
The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM2 supporting, PVS1 very strong, PP5 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PM2PVS1PP5PM5
Pathogenic
PALB2 c.682C>T
PM2 + PVS1 + PP5 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentPMID:17200671 ↗PMID:25099575 ↗PMID:28779002 ↗
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19573e-07; MAF= 0.00006%, 1/1614016 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 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 / 1,614,016
0 hom
0 hom
European (non-Finnish) 1 / 1,180,014 |
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
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic 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). BayesDel score = 0.63.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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; COSV55168872, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:17200671
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:25099575
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:28779002
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links