About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1351T>G, p.(Leu451Val)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is present at extremely low frequency in gnomAD v4.1 (AF = 0.00031%, 5/1,614,074 alleles), which is at or below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (≤1/300,000). Applied as PM2_Supporting per VCEP guidance.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
PALB2 VCEP v1.2.0 BP1 rule states: 'Apply to all missense variants.' This variant is a missense change (p.Leu451Val) in PALB2, a gene where primarily truncating variants are known to cause disease and missense pathogenic variants are thought to be exceedingly rare.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting benign; maps to Uncertain Significance - Conflicting Evidence.
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
5 / 1,614,074 alleles
gnomAD v4.1: 5 / 1,614,074 alleles. Recorded AF 3.09775e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19887e-05; MAF= 0.00120%, 3/250236 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89352e-05; MAF= 0.00289%, 1/34560 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55167320, n = 2 times).
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.
27 criteria with recorded statuses: 2 met · 7 not met · 0 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is a missense change (NM_024675.4:c.1351T>G, p.Leu451Val) in PALB2, a gene where loss of function is a known disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia type FA-N (autosomal recessive).
In gnomAD v4.1, the variant is present at extremely low frequency (AF = 0.00031%, 5/1,614,074 alleles; grpmax FAF = 7.9e-07), meeting the PALB2 VCEP PM2_Supporting threshold (≤0.000333%).
BP1_Supporting is applied per PALB2 VCEP rule: all missense variants in PALB2 receive BP1 because missense pathogenic variation is not yet confirmed as a disease mechanism and true pathogenic missense variants are thought to be exceedingly rare.
SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL (0.027) and BayesDel (-0.741) scores are consistent with a benign in silico profile, though PP3 and BP4 are not applied to missense variants per VCEP rules.
The variant has been observed in COSMIC in 2 somatic cancer samples but has no curated functional evidence from OncoKB.
ClinVar reports this variant as Uncertain significance (VariationID 951843, 2 clinical laboratories, criteria provided single submitter) with no expert panel classification.
No published literature specifically mentions NM_024675.4:c.1351T>G; all 16 PMIDs retrieved through ClinVar and literature searches were reviewed and none contain variant-specific evidence. All available full-text papers (PMID:34242744, 15604628, 17508274, 18163131) were confirmed to not mention this variant.
No co-segregation data, case-control studies, de novo reports, or functional studies are available for this variant. PS4, PP1, BS2, BS4, and PVS1 remain not assessed due to absence of evidence.
The only criteria met are PM2_Supporting (low population frequency) and BP1_Supporting (missense in PALB2). This yields a net of one pathogenic supporting and one benign supporting criterion — insufficient for classification beyond VUS per ACMG/AMP combination rules. The variant remains Uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThe variant is present at extremely low frequency in gnomAD v4.1 (AF = 0.00031%, 5/1,614,074 alleles), which is at or below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (≤1/300,000). Applied as PM2_Supporting per VCEP guidance. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 0.00031% (5/1
- 614
- 074)
- grpmax FAF = 7.9e-07
- Frequency meets PALB2 VCEP PM2_Supporting threshold (≤0.000333%)
Sources
BP1 SupportingPALB2 VCEP v1.2.0 BP1 rule states: 'Apply to all missense variants.' This variant is a missense change (p.Leu451Val) in PALB2, a gene where primarily truncating variants are known to cause disease and missense pathogenic variants are thought to be exceedingly rare. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP BP1 rule applies to all missense variants in PALB2
- PALB2 has a low rate of missense variants that are non-functional in relevant assays
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 PVS1 is not applicable to this missense variant (p.Leu451Val) per the PALB2 VCEP v1.2.0 PVS1 Decision Tree. SpliceAI predicts no splicing impact (max delta = 0.00), and no experimental evidence of a null effect (aberrant splicing or RNA defect) has been identified for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score of 0.00 confirms no predicted splicing impact
- Variant is a missense change (p.Leu451Val)
- not a null variant
Still missing
- No RNA or minigene functional studies available for this variant
Sources
PS4 No case-control study or cohort analysis demonstrating statistically increased prevalence of NM_024675.4:c.1351T>G in affected individuals has been identified. PALB2 VCEP PS4 requires a case-control study with p≤0.05 and OR≥3 or lower 95% CI ≥1.5. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain significance with no criterion-lead submissions
- No published case-control study identified for this variant
Still missing
- No proband counting or case-control data available
- ClinVar submissions do not include affected individual counts
Sources
PP1 No co-segregation data are available for this variant. PALB2 VCEP PP1 requires LOD score or Bayes Factor from quantitative co-segregation analysis; no family studies with this variant have been identified in the literature. Details ▾Hide ▴
Evidence considered
- No published co-segregation or family studies identified
Still missing
- No pedigree or LOD score data available
Sources
BA1 gnomAD v4.1 grpmax filtering allele frequency is 7.9e-07 (0.000079%), far below the PALB2 VCEP BA1 threshold of >0.1%. The variant is too rare to qualify as a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.000079%
- well below BA1 threshold of >0.1%
Sources
BS1 gnomAD v4.1 grpmax filtering allele frequency is 7.9e-07 (0.000079%), far below the PALB2 VCEP BS1 threshold of >0.01%. The variant frequency does not exceed expectation for disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.000079%
- well below BS1 threshold of >0.01%
Sources
BS2 No evidence of the variant observed in healthy adult individuals for a recessive (Fanconi anemia) disorder context. PALB2 VCEP BS2 requires Fanconi Anemia BS2 table-based point assignment; no qualifying proband data are available. Details ▾Hide ▴
Evidence considered
- No reported observations in healthy adults for recessive disorder assessment
Still missing
- No Fanconi Anemia BS2 proband data available
Sources
BS4 No segregation data demonstrating lack of co-segregation of this variant with disease in affected family members are available. PALB2 VCEP BS4 requires quantitative co-segregation analysis with LOD or Bayes Factor thresholds. Details ▾Hide ▴
Evidence considered
- No family studies or LOD scores demonstrating lack of segregation identified
Still missing
- No co-segregation data available for BS4 assessment
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APALB2 VCEP v1.2.0 explicitly states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' Details ▾Hide ▴
PS2 VCEPPALB2 VCEP v1.2.0 marks PS2 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' Details ▾Hide ▴
PS3 VCEPPALB2 VCEP v1.2.0 marks PS3 as not applicable; functional evidence for missense variants is directed to RNA-based PVS1 assessment rather than PS3. Details ▾Hide ▴
PM1 VCEPPALB2 VCEP v1.2.0 explicitly states: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' Details ▾Hide ▴
PM5 N/APALB2 VCEP v1.2.0 PM5 applies only to 'frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183' and explicitly states 'Do not use for missense changes.' This variant is a missense (p.Leu451Val). Details ▾Hide ▴
Evidence considered
- PALB2 VCEP PM5 rule is restricted to truncating variants upstream of p.Tyr1183
- not applicable to missense
Sources
PM6 VCEPPALB2 VCEP v1.2.0 marks PM6 as not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' Details ▾Hide ▴
PP2 VCEPPALB2 VCEP v1.2.0 explicitly states: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' Details ▾Hide ▴
PP3 N/APALB2 VCEP v1.2.0 PP3 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≥0.2. This is a missense variant with SpliceAI max delta of 0.00. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP PP3 excludes missense variants
- SpliceAI max delta = 0.00
- no splicing impact predicted
Sources
PP4 VCEPPALB2 VCEP v1.2.0 marks PP4 as not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity).' Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 deems PP4 not applicable for AD PALB2-related cancer predisposition
Sources
PP5 VCEPPALB2 VCEP v1.2.0 marks PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS3 VCEPPALB2 VCEP v1.2.0 marks BS3 as not applicable. Functional studies are directed to RNA-based PVS1/BP7 assessment rather than BS3. Details ▾Hide ▴
BP2 VCEPPALB2 VCEP v1.2.0 marks BP2 as not applicable. Details ▾Hide ▴
BP3 VCEPTrivially not applicable: variant is a substitution, not an in-frame deletion/insertion. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel
BP4 N/APALB2 VCEP v1.2.0 BP4 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≤0.1. This is a missense variant. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP BP4 excludes missense variants
- SpliceAI max delta = 0.00 confirms no splicing prediction applicable for BP4
Sources
BP5 VCEPPALB2 VCEP v1.2.0 marks BP5 as not applicable: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.' Details ▾Hide ▴
BP6 VCEPPALB2 VCEP v1.2.0 marks BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/APALB2 VCEP v1.2.0 BP7 is reserved for synonymous and deep intronic variants (further than +7 donor and -21 acceptor). This variant is a missense change (p.Leu451Val) and does not qualify. Details ▾Hide ▴
Evidence considered
- BP7 applies only to synonymous and deep intronic variants per VCEP
Sources
PS5 N/APS5 is not a criterion in the PALB2 VCEP v1.2.0 framework. The VCEP does not recognize PS5 as a valid criterion. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1351T>G
- Protein (HGVS p.)
- NP_078951.2:p.(Leu451Val)
- GRCh38
- chr16:23635195 A>C
- GRCh37
- chr16:23646516 A>C
- ClinVar
- 951843
- COSMIC
- COSV55167320
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
5 / 1,614,074 alleles
AF 3.1e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
3 / 250,236 alleles
AF 1.2e-05 · 0 homozygotes · FAF 2.94e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,614,074 alleles · 0 hom · FAF 7.9e-07
| Admixed American1 / 60,010 | 1.7e-05 |
| European (non-Finnish)4 / 1,180,002 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 250,236 alleles · 0 hom · FAF 2.9e-06
| Admixed American1 / 34,560 | 2.9e-05 |
| European (non-Finnish)2 / 112,958 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.09775e-06; MAF= 0.00031%, 5/1614074 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19887e-05; MAF= 0.00120%, 3/250236 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89352e-05; MAF= 0.00289%, 1/34560 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.027
- BayesDel
- -0.741
How the predictions were used
PP3 N/APALB2 VCEP v1.2.0 PP3 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≥0.2. This is a missense variant with SpliceAI max delta of 0.00. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP PP3 excludes missense variants
- SpliceAI max delta = 0.00
- no splicing impact predicted
Sources
BP4 N/APALB2 VCEP v1.2.0 BP4 rule states: 'Missense: Do not use.' The criterion is reserved for splicing variants with SpliceAI ≤0.1. This is a missense variant. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP BP4 excludes missense variants
- SpliceAI max delta = 0.00 confirms no splicing prediction applicable for BP4
Sources
BP7 N/APALB2 VCEP v1.2.0 BP7 is reserved for synonymous and deep intronic variants (further than +7 donor and -21 acceptor). This variant is a missense change (p.Leu451Val) and does not qualify. Details ▾Hide ▴
Evidence considered
- BP7 applies only to synonymous and deep intronic variants per VCEP
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.027. BayesDel score = -0.741444.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.Moyer VA et al. · 2014No paper-specific finding is recorded.
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PMID 24366402 ↗Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.2014No paper-specific finding is recorded.
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PMID 24432435 ↗PMID:24432435Nelson HD et al. · 2013No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
5 / 1,614,074 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
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/951843/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646516-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635195-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1351…
- OncoKB ↗www.oncokb.org/gene/PALB2/L451V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120587784
- 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= 3.09775e-06; MAF= 0.00031%, 5/1614074 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19887e-05; MAF= 0.00120%, 3/250236 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89352e-05; MAF= 0.00289%, 1/34560 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 951843)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.027. BayesDel score = -0.741444.
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; COSV55167320, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.