About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1652A>G, p.(Tyr551Cys)
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
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. This meets the CSPEC PM2_Supporting threshold of frequency ≤ 0.000333% (≤ 1/300,000) in gnomAD v4. Per CSPEC, PM2 is used at Supporting strength, not Moderate.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
CSPEC PALB2 v1.2.0 explicitly states: 'Apply to all missense variants.' Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are thought to be exceedingly rare. This rule applies to all missense variants, including p.Tyr551Cys.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 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; COSV99848424, 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.
29 criteria with recorded statuses: 2 met · 2 not met · 4 not assessed · 21 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_024675.4:c.1652A>G (p.Tyr551Cys) is a missense variant in PALB2, a gene where loss of function is an established disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia complementation group N (autosomal recessive).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations, meeting the CSPEC PM2_Supporting threshold of ≤ 0.000333% allele frequency (PM2_Supporting).
CSPEC PALB2 v1.2.0 applies BP1 (Supporting) to all missense variants, based on evidence that PALB2 has a very low rate of functional missense variants and true pathogenic missense changes are thought to be exceedingly rare (BP1_Supporting).
Multiple CSPEC criteria are explicitly not applicable to PALB2 missense variants: PS1, PM1, PM5, PP2, PP3, and BP4 are all prohibited by VCEP rules because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2.
PS3 and BS3 (functional studies) are marked not applicable by CSPEC; PS2 and PM6 (de novo) are not applicable; PP4 (phenotype specificity) and PP5 (reputable source) are not applicable for this VCEP; BP2, BP5, BP6, and BP7 are not applicable for this variant type.
PS4 (case-control), PP1 (co-segregation), BS2 (FA probands), and BS4 (lack of segregation) could not be assessed due to absence of clinical proband, segregation, or case-control data in the evidence set.
The variant has been reported in ClinVar as Uncertain Significance (VCV000856757) by 3 clinical laboratories with review status 'criteria provided, single submitter.' No expert panel classification is available.
No variant-specific functional or clinical evidence was identified in the literature. All PMIDs associated with this ClinVar entry are general guidelines or review articles (ACMG/AMP standards, genetic counseling recommendations, USPSTF statements) that do not mention NM_024675.4:c.1652A>G or p.Tyr551Cys.
Criterion summary: one pathogenic supporting criterion met (PM2_Supporting) and one benign supporting criterion met (BP1_Supporting). Per ACMG/AMP 2015 combining rules adopted by the CSPEC PALB2 framework (Rule31), the presence of both benign supporting and pathogenic supporting evidence results in a classification of Uncertain Significance with conflicting evidence.
No criteria match.
Met · 2
PM2 SupportingVariant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. This meets the CSPEC PM2_Supporting threshold of frequency ≤ 0.000333% (≤ 1/300,000) in gnomAD v4. Per CSPEC, PM2 is used at Supporting strength, not Moderate. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
BP1 SupportingCSPEC PALB2 v1.2.0 explicitly states: 'Apply to all missense variants.' Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are thought to be exceedingly rare. This rule applies to all missense variants, including p.Tyr551Cys. Details ▾Hide ▴
Evidence considered
- CSPEC BP1: Supporting — apply to all missense variants in PALB2
- Variant is a missense substitution (p.Tyr551Cys)
Sources
Not met · 2 · evaluated, threshold not reached
BA1 CSPEC BA1 requires Grpmax Filtering AF > 0.1% in gnomAD v4. The variant is absent from gnomAD v4.1 (0 alleles across all populations). BA1 threshold is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- frequency 0% — does not meet > 0.1% threshold
Sources
BS1 CSPEC BS1 requires Grpmax Filtering AF > 0.01% in gnomAD v4. The variant is absent from gnomAD v4.1 across all populations. BS1 threshold is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- frequency 0% — does not meet > 0.01% threshold
Sources
Not assessed · 4 · no assessment recorded
PS4 CSPEC PS4 requires case-control studies with p ≤ 0.05 AND (OR/HR/RR ≥ 3 OR lower 95% CI ≥ 1.5). No case-control study data is available for this variant. PS4_Moderate (proband counting) is explicitly not used per CSPEC. Details ▾Hide ▴
PP1 CSPEC PP1 requires quantitative co-segregation analysis (LOD scores or Bayes Factor LR) for AD disease or segregation in affected relatives for AR disease. No segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation data or LOD scores available
Still missing
- Segregation analysis not performed for this variant
Sources
BS2 CSPEC BS2 requires Fanconi Anemia BS2 proband point-counting tables (BS2_Strong ≥ 4 points, BS2_Moderate = 2 points, BS2_Supporting = 1 point). No Fanconi Anemia proband data available for this variant. Cannot be assessed without clinical proband information. Details ▾Hide ▴
Evidence considered
- No Fanconi Anemia proband data available
Still missing
- Fanconi Anemia proband data needed for BS2 point assignment
Sources
BS4 CSPEC BS4 requires quantitative co-segregation analysis (LOD ≤ -1.28 or LR ≤ 0.053 for Strong; LOD ≤ -0.64 or LR ≤ 0.23 for Moderate; LOD ≤ -0.32 or LR ≤ 0.48 for Supporting). No co-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation data or LOD scores available
Still missing
- Co-segregation analysis not performed for this variant
Sources
Not applicable · 21· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is a missense substitution (p.Tyr551Cys), not a null variant. The PALB2 PVS1 Decision Tree applies to nonsense, frameshift, and canonical splice site variants. SpliceAI max delta score of 0.03 confirms no cryptic splice impact that would trigger PVS1 consideration. Details ▾Hide ▴
Evidence considered
- Missense variant at codon 551
- variant bucket 'other'
- SpliceAI max delta 0.03
- no predicted splice alteration
Sources
pvs1_variant_assessmentspliceai ↗
PS1 N/ACSPEC PALB2 v1.2.0 explicitly states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 Splicing table applies only to splicing variants, not missense substitutions without splice impact. Details ▾Hide ▴
PS2 VCEPCSPEC PALB2 v1.2.0 marks PS2 as not applicable: de novo occurrences have not yet been observed for PALB2 autosomal dominant disease. Details ▾Hide ▴
PS3 VCEPCSPEC PALB2 v1.2.0 marks PS3 as not applicable for this VCEP. Functional protein assays are not validated for PALB2 missense variant assessment. Details ▾Hide ▴
PM1 VCEPCSPEC PALB2 v1.2.0 states: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' PM1 (mutational hotspot / critical domain) is not applicable for PALB2 missense variants. Details ▾Hide ▴
Evidence considered
- CSPEC PM1: Not applicable — missense pathogenic variation not confirmed in PALB2
Sources
PM3 N/ASkipped per user instruction. CSPEC PM3 requires Fanconi Anemia proband point-counting tables — no FA trans configuration data available in evidence set. Details ▾Hide ▴
Evidence considered
- Skipped per user directive
PM4 VCEPCSPEC PALB2 v1.2.0 limits PM4 to stop-loss variants only. This variant is a single-nucleotide missense substitution, not a stop-loss variant. Details ▾Hide ▴
PM5 N/ACSPEC PALB2 v1.2.0 states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5_Supporting rule applies only to truncating variants upstream of p.Tyr1183 or splice variants. This is a missense substitution. Details ▾Hide ▴
Evidence considered
- CSPEC PM5: Do not use for missense
- PM5_Supporting applies only to truncating/splice variants upstream of p.Tyr1183
Sources
cspec ↗pm5_candidates
PM6 VCEPCSPEC PALB2 v1.2.0 marks PM6 as not applicable: informative de novo occurrences have not yet been observed for PALB2 AD or AR disease. Details ▾Hide ▴
PP2 VCEPCSPEC PALB2 v1.2.0 states: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 is reserved for genes where missense variants are a common disease mechanism, which is not established for PALB2. Details ▾Hide ▴
Evidence considered
- CSPEC PP2: Not applicable — missense not confirmed as disease mechanism in PALB2
Sources
PP3 N/ACSPEC PALB2 v1.2.0 states: 'Missense: Do not use.' In silico predictors have not been validated for PALB2 missense variant functional outcome. SpliceAI max delta 0.03 is well below the 0.2 threshold, REVEL 0.007 and BayesDel -0.668 both predict benign, but PP3 is not applied to missense variants per VCEP rules. Details ▾Hide ▴
Evidence considered
- CSPEC PP3: Missense — do not use
- REVEL score 0.007 (benign)
- BayesDel score -0.668 (benign)
- SpliceAI max delta 0.03 (< 0.2 threshold)
Sources
PP4 VCEPCSPEC PALB2 v1.2.0 states PP4 is not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.' Details ▾Hide ▴
PP5 VCEPCSPEC PALB2 v1.2.0 states: 'Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BS3 VCEPCSPEC PALB2 v1.2.0 marks BS3 as not applicable for this VCEP. Functional benign assays are not validated for PALB2 missense variants. Details ▾Hide ▴
BP2 VCEPCSPEC PALB2 v1.2.0 marks BP2 as not applicable. Observed in trans/cis with a pathogenic variant is assessed via the ATM PM3/BP2 table, not independently for PALB2. Details ▾Hide ▴
BP3 VCEPVariant is a single-nucleotide missense substitution, not an in-frame deletion/insertion. CSPEC also marks BP3 as not applicable for PALB2. Details ▾Hide ▴
BP4 N/ACSPEC PALB2 v1.2.0 states: 'Missense: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants.' Although SpliceAI max delta 0.03 indicates no predicted splice impact and both REVEL (0.007) and BayesDel (-0.668) predict benign, BP4 is not applied to missense variants per VCEP rules. Details ▾Hide ▴
Evidence considered
- CSPEC BP4: Missense — do not use
- SpliceAI max delta 0.03 (no predicted splice impact)
- REVEL 0.007 (benign)
- BayesDel -0.668 (benign)
Sources
BP5 VCEPCSPEC PALB2 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 VCEPCSPEC PALB2 v1.2.0 states: 'Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP7 N/ACSPEC BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This variant is a missense substitution (c.1652A>G, p.Tyr551Cys), not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 reserved for synonymous and deep intronic variants
Sources
PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework (PMID:25741868) or the PALB2 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG/AMP criterion
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1652A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Tyr551Cys)
- GRCh38
- chr16:23634894 T>C
- GRCh37
- chr16:23646215 T>C
- ClinVar
- 856757
- COSMIC
- COSV99848424
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.007
- BayesDel
- -0.668
How the predictions were used
PP3 N/ACSPEC PALB2 v1.2.0 states: 'Missense: Do not use.' In silico predictors have not been validated for PALB2 missense variant functional outcome. SpliceAI max delta 0.03 is well below the 0.2 threshold, REVEL 0.007 and BayesDel -0.668 both predict benign, but PP3 is not applied to missense variants per VCEP rules. Details ▾Hide ▴
Evidence considered
- CSPEC PP3: Missense — do not use
- REVEL score 0.007 (benign)
- BayesDel score -0.668 (benign)
- SpliceAI max delta 0.03 (< 0.2 threshold)
Sources
BP4 N/ACSPEC PALB2 v1.2.0 states: 'Missense: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants.' Although SpliceAI max delta 0.03 indicates no predicted splice impact and both REVEL (0.007) and BayesDel (-0.668) predict benign, BP4 is not applied to missense variants per VCEP rules. Details ▾Hide ▴
Evidence considered
- CSPEC BP4: Missense — do not use
- SpliceAI max delta 0.03 (no predicted splice impact)
- REVEL 0.007 (benign)
- BayesDel -0.668 (benign)
Sources
BP7 N/ACSPEC BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This variant is a missense substitution (c.1652A>G, p.Tyr551Cys), not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 reserved for synonymous and deep intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.007. BayesDel score = -0.668197.
6 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 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for sequence variant interpretation. General framework paper that does not mention PALB2 or any specific variant.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004Genetic cancer risk assessment and counseling recommendations from the National Society of Genetic Counselors. General guideline document that does not mention specific PALB2 variants.Does not name this variant
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993GeneReviews entry on BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. Gene-level clinical summary that does not discuss PALB2 or specific PALB2 variants.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Risk Assessment and Counseling summary. General reference document with no abstract or variant-specific content available.Does not name this variant
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PMID 31429903 ↗Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.USPSTF recommendation statement on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Mentions PALB2 once in the context of multigene testing panels. Does not mention NM_024675.4:c.1652A>G or p.Tyr551Cys.Does not name this variant
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PMID 31479213 ↗PMID 31479213No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
3 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/856757/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646215-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23634894-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-23634894-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1652…
- OncoKB ↗www.oncokb.org/gene/PALB2/Y551C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120592967
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 856757)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.007. BayesDel score = -0.668197.
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; COSV99848424, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.