About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2014G>C, p.(Glu672Gln)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
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.
BP1Supporting
BP1 · supporting
This variant meets BP1 because it is a missense substitution, and the PALB2 VCEP specification applies BP1 to all missense variants.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
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.
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
43,792 / 1,614,144 alleles
gnomAD v4.1: 43,792 / 1,614,144 alleles. Recorded AF 0.0271302. Recorded homozygote count 715.
gnomAD 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.
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.
Functional evidence
Statement recorded
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.
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: 3 met · 2 not met · 6 not assessed · 17 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.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.
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%.
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.
No criteria match.
Met · 3
BA1 Stand aloneThis 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. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- PALB2 BA1 threshold is grpmax filtering AF >0.1% in gnomAD v4
- Observed gnomAD v4 frequency is markedly above threshold
Sources
BP1 SupportingThis variant meets BP1 because it is a missense substitution, and the PALB2 VCEP specification applies BP1 to all missense variants. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- PALB2 VCEP instructs BP1 for all missense variants
Sources
Not met · 2 · evaluated, threshold not reached
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. Available evidence supports PALB2 loss of function as a disease mechanism, but this specific variant is not a null variant and does not meet PVS1. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 VCEP includes PVS1 guidance
- Generic PVS1 scaffold does not place this variant in a nonsense
- frameshift
- or canonical splice bucket
Sources
PM2 This variant is far more common than the PALB2 PM2 threshold. In gnomAD v4.1, the allele frequency is 2.71302% with grpmax filtering allele frequency 5.70171%, which is well above the PM2 threshold of ≤0.000333%. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- PALB2 PM2_Supporting threshold is frequency ≤1/300
- 000 in gnomAD v4
- Observed gnomAD v4 frequency greatly exceeds threshold
Sources
Not assessed · 6 · no assessment recorded
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. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- PALB2 PS4 requires case-control statistics at the stated threshold
- Reviewed literature triage did not provide qualifying variant-specific enrichment data
Still missing
- No qualifying variant-specific case-control statistics were identified
Sources
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. Details ▾Hide ▴
Rule
See Fanconi Anemia PM3 tables for approach to assign points per proband.
Evidence considered
- PALB2 PM3 requires Fanconi anemia point-based evidence
- No qualifying phase-confirmed proband data were identified
Still missing
- No qualifying in-trans Fanconi anemia observations were identified
Sources
PP1 No segregation data were identified that meet the PALB2 VCEP quantitative thresholds for PP1. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 / 0.60 / 1.26 or Bayes Factor ≥2:1 / 4:1 / 18:1; AR: segregation in 1 / 2 / ≥3 affected relatives
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence
- No qualifying segregation dataset was identified
Still missing
- No qualifying segregation or Bayes factor data were identified
Sources
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. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- Observed gnomAD v4 frequency exceeds both BS1 and BA1 thresholds
- BA1 supersedes the need to count BS1 separately
Sources
BS2 No qualifying PALB2 Fanconi anemia BS2 point-based data were identified. Although this variant is seen in many gnomAD individuals, including homozygotes, the reviewed materials do not provide the phenotyped proband-level evidence required for BS2 under the PALB2 specification. Details ▾Hide ▴
Rule
See Fanconi Anemia BS2 tables for approach to assign points per proband.
Evidence considered
- PALB2 BS2 uses a point-based Fanconi anemia framework
- Population homozygote counts alone do not satisfy the specified BS2 framework here
Still missing
- No qualifying phenotyped proband data meeting PALB2 BS2 point rules were identified
Sources
BS4 No quantitative non-segregation data were identified that meet the PALB2 VCEP BS4 thresholds. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤0.053:1; lower thresholds for Moderate and Supporting
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence
Still missing
- No qualifying LOD score or Bayes factor data for non-segregation were identified
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APALB2 VCEP PS1 guidance is directed to the PALB2 PS1 splicing table. This missense substitution does not have evidence here supporting a same-splice-effect PS1 application. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- PALB2 PS1 specification is splicing-table based
- SpliceAI predicts no meaningful splice effect
Sources
PS2 N/AThis criterion is not applicable in the PALB2 VCEP specification for this context. Details ▾Hide ▴
PS3 N/AThis criterion is not applicable in the PALB2 VCEP specification. No qualifying PALB2 VCEP functional framework for PS3 use was identified for this missense variant in the reviewed materials. Details ▾Hide ▴
PM1 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PM4 N/APALB2 VCEP does not apply PM4 to missense variants. This variant is not a stop-loss variant. Details ▾Hide ▴
PM5 N/APALB2 VCEP PM5 applies to truncating or qualifying splice variants predicted to cause loss of function upstream of p.Tyr1183. This missense substitution does not meet that variant-type requirement. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183; apply to qualifying splice variants similarly.
Evidence considered
- PALB2 PM5 is restricted to truncating or qualifying splice loss-of-function events
- This variant is a missense substitution
Sources
cspec ↗pvs1_variant_assessment
PM6 N/AThis criterion is not applicable in the PALB2 VCEP specification for this context. Details ▾Hide ▴
PP2 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PP3 N/APALB2 VCEP does not use PP3 for missense variants. Although SpliceAI shows no predicted splice effect (max delta score 0.01), and REVEL 0.029 and BayesDel -0.736359 do not suggest a damaging effect, the PALB2 VCEP specification states that missense PP3 should not be applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
- PP3 is restricted to splicing predictions outside canonical splice sites in this PALB2 specification
- Missense PP3 is explicitly disallowed
- Available computational results do not show a splice-damaging pattern
Sources
PP4 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PP5 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BS3 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP2 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP3 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP4 N/APALB2 VCEP does not use BP4 for missense variants. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and REVEL 0.029 and BayesDel -0.736359 are consistent with a benign computational profile, but the PALB2 VCEP specification states that missense BP4 should not be applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- BP4 is limited to splicing prediction for non-missense use in this PALB2 specification
- Missense BP4 is explicitly disallowed
- Available computational results do not suggest splice disruption
Sources
BP5 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous and deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This variant is a missense substitution and does not meet the PALB2 BP7 variant-type requirements. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based BP7 may be applied for observed lack of aberrant RNA defect.
Evidence considered
- PALB2 BP7 is restricted to synonymous and deep intronic settings
- This variant is missense
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2014G>C
- Protein (HGVS p.)
- NP_078951.2:p.(Glu672Gln)
- GRCh38
- chr16:23630140 C>G
- GRCh37
- chr16:23641461 C>G
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.3. Select a row to find it on the plot.
PALB2NM_024675.3
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
43,792 / 1,614,144 alleles
AF 0.0271 · 715 homozygotes · FAF 0.057
gnomAD v2.1
6,337 / 282,818 alleles
AF 0.0224 · 108 homozygotes · FAF 0.0285
By genetic ancestry
gnomAD v4.1
AF 0.027 · 43792 / 1,614,144 alleles · 715 hom · FAF 0.057
| Amish140 / 912 | 0.1512 hom |
| Middle Eastern377 / 6,062 | 0.06218 hom |
| Ashkenazi Jewish1093 / 29,600 | 0.03722 hom |
| European (non-Finnish)35343 / 1,180,024 | 0.03536 hom |
| Remaining individuals1708 / 62,502 | 0.02733 hom |
| South Asian2345 / 91,080 | 0.02670 hom |
| European (Finnish)1237 / 64,026 | 0.01910 hom |
| Admixed American1125 / 60,006 | 0.01912 hom |
| African/African American416 / 75,050 | 0.00552 hom |
| East Asian8 / 44,882 | 0.00018 |
gnomAD v2.1
AF 0.022 · 6337 / 282,818 alleles · 108 hom · FAF 0.028
| Ashkenazi Jewish363 / 10,370 | 0.0354 hom |
| European (non-Finnish)3773 / 129,156 | 0.02970 hom |
| Remaining individuals197 / 7,220 | 0.0274 hom |
| South Asian813 / 30,616 | 0.02721 hom |
| European (Finnish)500 / 25,110 | 0.022 hom |
| Admixed American553 / 35,434 | 0.0166 hom |
| African/African American136 / 24,960 | 0.00541 hom |
| East Asian2 / 19,952 | 0.0001 |
Statements
gnomAD 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.
gnomAD 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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APALB2 VCEP does not use PP3 for missense variants. Although SpliceAI shows no predicted splice effect (max delta score 0.01), and REVEL 0.029 and BayesDel -0.736359 do not suggest a damaging effect, the PALB2 VCEP specification states that missense PP3 should not be applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
- PP3 is restricted to splicing predictions outside canonical splice sites in this PALB2 specification
- Missense PP3 is explicitly disallowed
- Available computational results do not show a splice-damaging pattern
Sources
BP4 N/APALB2 VCEP does not use BP4 for missense variants. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and REVEL 0.029 and BayesDel -0.736359 are consistent with a benign computational profile, but the PALB2 VCEP specification states that missense BP4 should not be applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- BP4 is limited to splicing prediction for non-missense use in this PALB2 specification
- Missense BP4 is explicitly disallowed
- Available computational results do not suggest splice disruption
Sources
BP7 N/ABP7 is intended for synonymous and deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This variant is a missense substitution and does not meet the PALB2 BP7 variant-type requirements. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based BP7 may be applied for observed lack of aberrant RNA defect.
Evidence considered
- PALB2 BP7 is restricted to synonymous and deep intronic settings
- This variant is missense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.736359.
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
43,792 / 1,614,144 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/126630/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641461-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23630140-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2014…
- OncoKB ↗www.oncokb.org/gene/PALB2/E672Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107874940
- 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= 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 v2.1
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.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55161919, n = 30 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.