About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2234A>G, p.(Lys745Arg)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
This variant is present in gnomAD v4.1 with a highest observed African/African American allele frequency of 0.01602% (12/74,906), which is above the PALB2 BS1 threshold of 0.01%, supporting BS1.
BP1Supporting
BP1 · supporting
This variant is a missense change, and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for PALB2.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework; Rule18 applies.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
13 / 1,614,018 alleles
gnomAD v4.1: 13 / 1,614,018 alleles. Recorded AF 8.05443e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19287e-05; MAF= 0.00119%, 3/251494 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000184547; MAF= 0.01845%, 3/16256 alleles, homozygotes = 0); grpmax FAF= 4.977e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 5 not assessed · 19 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PALB2 c.2234A>G (p.Lys745Arg, p.K745R) variant has been reported in ClinVar with conflicting interpretations, including uncertain significance and likely benign submissions.
In population data, this variant is present in gnomAD v4.1 at 13/1,614,018 alleles overall (0.00081%) with a highest observed African/African American frequency of 12/74,906 alleles (0.01602%), which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.
Under the PALB2 specification, BP1 applies because this is a missense variant in a gene where truncating variants are the predominant established disease mechanism.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02; however, PP3 and BP4 are not applied to missense variants in the PALB2 framework.
No criteria match.
Met · 2
BS1 StrongThis variant is present in gnomAD v4.1 with a highest observed African/African American allele frequency of 0.01602% (12/74,906), which is above the PALB2 BS1 threshold of 0.01%, supporting BS1. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 0.0001602008 (0.01602%)
- 12/74
- 906 alleles
- 0 homozygotes.
- PALB2 VCEP BS1 threshold: grpmax filtering AF >0.01% in gnomAD v4.
Sources
BP1 SupportingThis variant is a missense change, and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for PALB2. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.4:c.2234A>G causes p.(Lys745Arg)
- a missense substitution.
- PALB2 VCEP BP1 rule: apply to all missense variants.
Sources
Not met · 2 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 at 0.00081% (13/1,614,018 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset for PM2_Supporting.
Evidence considered
- gnomAD v4.1 total AF = 0.0000080544 (0.00081%)
- 13/1
- 614
- 018 alleles
- 0 homozygotes.
- PALB2 VCEP PM2 threshold: frequency ≤1/300
- 000 (0.000333%) in gnomAD v4.
Sources
BA1 The highest observed gnomAD v4.1 allele frequency is 0.01602% (12/74,906), which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 0.01602%.
- PALB2 VCEP BA1 threshold: grpmax filtering AF >0.1% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 ClinVar shows conflicting laboratory classifications, but no qualifying PALB2 case-control study with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 3 was identified, so PS4 cannot be assessed. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- PALB2 VCEP PS4 requires case-control data meeting statistical thresholds.
- ClinVar contains conflicting submissions but does not provide qualifying PS4 case-control evidence.
Still missing
- No qualifying case-control data were identified.
Sources
PM3 No Fanconi anemia proband or confirmed in-trans data were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3_Supporting = 1 point; PM3 = 2 points; PM3_Strong ≥4 points; PM3_VeryStrong ≥8 points.
Evidence considered
- PALB2 VCEP PM3 requires point-based in-trans evidence in affected probands.
Still missing
- No phase-confirmed recessive observations were identified.
Sources
PP1 No informative co-segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD condition: LOD ≥0.3 / 0.60 / 1.26 or Bayes Factor ≥2:1 / 4:1 / 18:1 for supporting/moderate/strong.
Evidence considered
- PALB2 VCEP PP1 requires quantitative segregation evidence.
Still missing
- No family-based segregation data with a calculable LOD score or Bayes factor were identified.
Sources
BS2 No qualifying observations in unaffected adults or Fanconi-anemia-specific BS2 point data were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2_Strong ≥4 points.
Evidence considered
- PALB2 VCEP BS2 uses point-based evidence and excludes population datasets such as gnomAD.
Still missing
- No eligible unaffected adult observations with required context were identified.
Sources
BS4 No quantitative segregation or lack-of-segregation data were identified, so BS4 cannot be assessed for this variant. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤0.053:1 for BS4_Strong; weaker negative segregation thresholds for moderate or supporting.
Evidence considered
- PALB2 VCEP BS4 requires quantitative lack-of-segregation evidence.
Still missing
- Quantitative segregation evidence such as LOD score or Bayes factor was not available.
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ALoss of function is an established PALB2 disease mechanism, but this variant is a missense substitution outside the PVS1 null-variant categories, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, so PVS1 is not applicable. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- PALB2 is eligible for PVS1 at the gene level.
- Variant assessment does not place c.2234A>G in a nonsense
- frameshift
- or canonical ±1/2 splice bucket.
- SpliceAI max delta score = 0.02.
Sources
PS1 N/APS1 is not applicable because the PALB2 specification does not use PS1 for missense changes and reserves it for qualifying splicing-table evidence. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table; missense do not use.
Evidence considered
- PALB2 VCEP PS1: missense do not use
- splicing only via PALB2 PS1 table.
Sources
PS2 N/APS2 is not applicable under the PALB2 specification. Details ▾Hide ▴
PS3 N/APS3 is not applicable under the PALB2 specification for this review context. Details ▾Hide ▴
PM1 N/APM1 is not applicable under the PALB2 specification because missense pathogenicity in PALB2 is not an established mechanism for using hotspot or critical-domain evidence. Details ▾Hide ▴
PM4 N/AThis is a missense substitution and not a stop-loss variant, so PM4 is not applicable under the PALB2 specification. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP states PM4 is used for stop-loss variants
- not missense substitutions.
Sources
PM5 N/APM5 is not applicable because the PALB2 specification does not use PM5 for missense changes. Details ▾Hide ▴
Rule
PM5_Supporting is reserved for qualifying truncating or certain splice variants, not missense variants.
Evidence considered
- PALB2 VCEP PM5: do not use for missense changes.
Sources
PM6 N/APM6 is not applicable under the PALB2 specification. Details ▾Hide ▴
PP2 N/APP2 is not applicable because missense pathogenicity is not an established PALB2 mechanism for this rule. Details ▾Hide ▴
PP3 N/ASpliceAI does not predict a splice effect for this variant, with a maximum delta score of 0.02, and the PALB2 specification does not apply PP3 to missense variants, so PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only: SpliceAI ≥0.2 for eligible non-canonical splice-impact variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- PALB2 VCEP PP3: missense do not use
- splicing requires SpliceAI ≥0.2.
Sources
PP4 N/APP4 is not applicable for PALB2 hereditary breast, ovarian, and pancreatic cancer because the phenotype is not sufficiently specific for a single genetic etiology. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP marks PP4 as not applicable for the dominant cancer phenotype context.
Sources
PP5 N/APP5 is not used by this VCEP. Details ▾Hide ▴
BS3 N/ABS3 is not applicable under the PALB2 specification for this review context. Details ▾Hide ▴
BP2 N/ABP2 is not applicable under the PALB2 specification. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable under the PALB2 specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only: no predicted impact via SpliceAI ≤0.1, and do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- PALB2 VCEP BP4: do not apply for missense variants.
Sources
BP5 N/ABP5 is not applicable under the PALB2 specification. Details ▾Hide ▴
BP6 N/ABP6 is not used by this VCEP. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or deep intronic, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP BP7 applies to synonymous and certain deep intronic variants or RNA evidence for those classes.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.2234A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Lys745Arg)
- GRCh38
- chr16:23629920 T>C
- GRCh37
- chr16:23641241 T>C
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PALB2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
13 / 1,614,018 alleles
AF 8.05e-06 · 0 homozygotes · FAF 9.22e-05
gnomAD v2.1
3 / 251,494 alleles
AF 1.19e-05 · 0 homozygotes · FAF 4.98e-05
By genetic ancestry
gnomAD v4.1
AF 8.1e-06 · 13 / 1,614,018 alleles · 0 hom · FAF 9.2e-05
| African/African American12 / 74,906 | 0.00016 |
| Remaining individuals1 / 62,486 | 1.6e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 1.2e-05 · 3 / 251,494 alleles · 0 hom · FAF 5e-05
| African/African American3 / 16,256 | 0.00018 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.05443e-06; MAF= 0.00081%, 13/1614018 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160201; MAF= 0.01602%, 12/74906 alleles, homozygotes = 0); grpmax FAF= 9.216e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19287e-05; MAF= 0.00119%, 3/251494 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000184547; MAF= 0.01845%, 3/16256 alleles, homozygotes = 0); grpmax FAF= 4.977e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI does not predict a splice effect for this variant, with a maximum delta score of 0.02, and the PALB2 specification does not apply PP3 to missense variants, so PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only: SpliceAI ≥0.2 for eligible non-canonical splice-impact variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- PALB2 VCEP PP3: missense do not use
- splicing requires SpliceAI ≥0.2.
Sources
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only: no predicted impact via SpliceAI ≤0.1, and do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- PALB2 VCEP BP4: do not apply for missense variants.
Sources
BP7 N/AThis variant is missense rather than synonymous or deep intronic, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP BP7 applies to synonymous and certain deep intronic variants or RNA evidence for those classes.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
13 / 1,614,018 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1526222356
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/480232/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641241-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23629920-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.2234…
- OncoKB ↗www.oncokb.org/gene/PALB2/K745R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2234A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.05443e-06; MAF= 0.00081%, 13/1614018 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160201; MAF= 0.01602%, 12/74906 alleles, homozygotes = 0); grpmax FAF= 9.216e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19287e-05; MAF= 0.00119%, 3/251494 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000184547; MAF= 0.01845%, 3/16256 alleles, homozygotes = 0); grpmax FAF= 4.977e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (3 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.