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PALB2c.1049_1051delinsTTCTPathogenic
Print report
Variant interpretation report

PALB2 c.1049_1051delinsTTCT, p.(Gln350LeufsTer11)

NM_024675.4:c.1049_1051delinsTTCT NP_078951.2:p.(Gln350LeufsTer11) Frameshift · exon 4 View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PALB2

PALB2 encodes a tumor suppressor protein that partners with BRCA2 (and also interacts with BRCA1) to repair double-stranded DNA breaks through the homologous recombination pathway. It acts as a scaffold that stabilizes BRCA2 in the cell nucleus and helps recruit DNA-repair machinery to sites of damage. Inherited mutations in PALB2 increase susceptibility to breast cancer, with smaller associated risks for ovarian, pancreatic, and prostate cancer and melanoma, and inheriting two mutated copies causes Fanconi anemia complementation group N. Rare somatic alterations in PALB2 are also found across various tumor types.

NCBI Gene ↗ OncoKB ↗
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 v1.3. 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Met, very strong: frameshift p.(Q350Lfs*11) creates a premature stop 11 codons after Gln350 in coding exon 4, well upstream of p.His1184.

PM2Supporting
PM2 · supporting

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PALB2 PM2 threshold of <=0.000333%.

PM5Supporting
PM5 · supporting

Met, supporting: PALB2 PM5 applies to NMD-prone PVS1-very-strong truncations upstream of His1184, and this Q350 frameshift terminates near residue 360.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 (very strong) plus PM2 and PM5 (supporting) satisfy Rule4 of the PALB2 VCEP Version 1.3 framework.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.013 maximum delta

Recorded SpliceAI maximum delta score: 0.013. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PALB2 VCEP v1.3, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 2 not met · 5 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The PALB2 Version 1.3 VCEP framework governs this assessment. PS4 cannot be established from an aggregate truncating-variant case-control result because the queried exact variant was not reported; PP4, PP5, BP5, and BP6 are explicitly not applicable under the VCEP.

No exact-variant ClinVar expert-panel assertion was found, so neither PP5 nor BP6 is triggered.

All three requested criteria are not applicable because the variant consequence is frameshift, p.(Gln350LeufsTer11), rather than missense, splice-region/intronic, or synonymous.

No SpliceAI, REVEL, BayesDel, or other computational predictor was evaluated because the requested criteria are out of scope for this truncating variant.

Met · 3

PVS1 Very strongMet, very strong: frameshift p.(Q350Lfs*11) creates a premature stop 11 codons after Gln350 in coding exon 4, well upstream of p.His1184. Details ▾Hide ▴
Reasoning

PVS1 is met at very strong strength. NM_024675.4:c.1049_1051delinsTTCT is a frameshift producing NP_078951.2:p.(Q350Lfs*11), a premature termination codon 11 codons after Gln350. The variant is in coding exon 4 of the PALB2 transcript variant 1, and the PALB2 VCEP states that its default disease-relevant transcript is NM_024675.3/ENST00000261584.8 and that described alternate isoforms are not candidate rescue transcripts. PALB2 loss of function is an established disease mechanism; the truncation is far from the extreme 3' end and is expected to be NMD-prone, with the premature termination occurring well upstream of the VCEP p.His1184 cutoff. The PALB2 VCEP v1.3 PVS1 guidance directs use of its PVS1 decision tree for frameshift variants, and no named VCEP or ClinGen SVI downgrade rule applies here.

Rule
PALB2 VCEP Version 1.3 PVS1 Decision Tree with generic ClinGen SVI PVS1 framework; no downgrade triggered
Evidence considered
  • PALB2 VCEP Version 1.3 identifies frameshift variants as PVS1-eligible null variants and directs use of the PALB2 PVS1 decision tree.
  • The normalized consequence is NM_024675.4:c.1049_1051delinsTTCT, NP_078951.2:p.(Q350Lfs*11), with the variant located in coding exon 4.
  • The PALB2 VCEP states that the default disease-relevant transcript is NM_024675.3/ENST00000261584.8 and that described alternate isoforms are not candidate rescue transcripts.
  • The PALB2 VCEP PVS1 rule applies PM5-supporting only to NMD-prone truncating variants with premature termination codons upstream of p.His1184; this variant terminates at approximately p.360.
  • ClinGen SVI PVS1 guidance supports full-strength PVS1 for an NMD-prone truncating variant when no transcript, exon-importance, distal-region, or escape-from-NMD downgrade applies.
Sources
cspec ↗vcep_palb2_pvs1_v1_3pvs1_generic_framework ↗
PM2 SupportingMet at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PALB2 PM2 threshold of <=0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP requires PM2 at supporting strength when the variant frequency is no greater than 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency. The variant is absent from gnomAD v2.1 and gnomAD v4.1, including the available non-cancer searches, so its observed frequency is 0 and satisfies the threshold.

Rule
PM2 Supporting: frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; if >0.000333% but n=1 in only one subpopulation, PM2 Supporting may still apply.
Evidence considered
  • The PALB2 VCEP Version 1.3 specifies PM2 Supporting at frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency.
  • The variant is absent from gnomAD v2.1 and gnomAD v4.1; the observed allele frequency is therefore 0, below the VCEP threshold.
  • The available gnomAD non-cancer searches also report absence; the VCEP does not require a non-cancer-only or exome-only source for this rule, so the all-comers gnomAD entries are the governing default.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 SupportingMet, supporting: PALB2 PM5 applies to NMD-prone PVS1-very-strong truncations upstream of His1184, and this Q350 frameshift terminates near residue 360. Details ▾Hide ▴
Reasoning

The PALB2 VCEP expands PM5_supporting beyond classic same-residue missense comparisons: it applies to NMD-prone truncating variants receiving PVS1 at Very Strong when the premature termination codon is upstream of p.His1184. This variant is a frameshift producing p.(Q350Lfs*11), placing the premature termination codon at approximately residue 360, well upstream of p.His1184; PALB2 loss of function is an established disease mechanism and the case assessment supports the full-strength PVS1 framework. Therefore PM5 at supporting strength is met under the governing VCEP rule, despite the absence of a classic same-residue missense comparator.

Rule
PM5_supporting: apply to NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.His1184.
Evidence considered
  • The PALB2 VCEP PM5 rule assigns supporting evidence to NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.His1184.
  • The variant is NM_024675.4:c.1049_1051delinsTTCT, annotated as NP_078951.2:p.(Q350Lfs*11), so the premature termination occurs around residue 360, upstream of His1184.
  • The PALB2 VCEP PVS1 materials establish the loss-of-function framework for PALB2, and the case PVS1 assessment identifies this as a frameshift evaluated under that framework with a suggested default strength of very strong.
Sources
cspec ↗vcep_palb2_pvs1_v1_3pvs1_variant_assessment

Not met · 2 · evaluated, threshold not reached

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PALB2 VCEP BA1 threshold of >0.1% group-maximum filtering allele frequency. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies BA1 as stand-alone benign when the gnomAD group maximum filtering allele frequency is greater than 0.1%. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency reaches the BA1 threshold.

Rule
Grpmax Filtering AF >0.1% in gnomAD
Evidence considered
  • The PALB2 VCEP Version 1.3 rule requires group-maximum filtering AF >0.1% in gnomAD for BA1.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; therefore its observed allele frequency is below the BA1 threshold.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PALB2 VCEP BS1 threshold of >0.01% group-maximum filtering allele frequency. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies BS1 at strong strength when the gnomAD group maximum filtering allele frequency is greater than 0.01%. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency reaches the BS1 threshold.

Rule
Grpmax Filtering AF >0.01% in gnomAD
Evidence considered
  • The PALB2 VCEP Version 1.3 rule requires group-maximum filtering AF >0.01% in gnomAD for BS1.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; therefore its observed allele frequency is below the BS1 threshold.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 Not assessed: aggregate PALB2 truncating variants had OR 4.69, but the study did not report this exact variant. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PS4 rule requires a case-control study with p-value <=.05 and (odds ratio, hazard ratio, or relative risk >=3 or lower 95% CI >=1.5). PMID:28779002 reports aggregate PALB2 truncating-variant enrichment (OR=4.69, 95% CI 2.27 to 9.68, p=6.9x10^-6) in 13,087 breast-cancer cases and 5,488 controls, but explicitly does not mention NM_024675.4:c.1049_1051delinsTTCT or p.(Q350Lfs*11). Therefore, the aggregate truncating-variant result cannot establish prevalence of this exact variant, and PS4 is not assessed. The literal governing comparisons are p-value <=.05 and OR >=3 or lower 95% CI >=1.5; for the reported aggregate OR: 4.69 >= 3? yes; p=6.9x10^-6 <= .05? yes; however these values are not exact-variant estimates.

Rule
Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=3 or lower 95% CI >=1.5).
Evidence considered
  • PALB2 VCEP Version 1.3 PS4 rule: "Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=3 or lower 95% CI >=1.5)."
  • PMID:28779002 studied 13,087 breast-cancer cases and 5,488 controls and reported aggregate truncating PALB2 variants with OR=4.69, 95% CI 2.27 to 9.68, p=6.9x10^-6, but the queried c.1049_1051delinsTTCT variant was not mentioned.
Still missing
  • An exact-variant case-control count or exact-variant enrichment estimate with the required statistical significance and confidence interval is unavailable.
Sources
cspec ↗PMID:28779002 ↗
PM3 Not assessed: no affected Fanconi-anemia proband or documented second pathogenic PALB2 allele with confirmed trans phase is available for the VCEP's 1–8-point PM3 framework. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PM3 for Fanconi anemia, an autosomal-recessive PALB2 disorder, using proband points based on phenotype and zygosity/phase: 2 points for a phenotype-consistent affected proband with the variant confirmed in trans with a pathogenic variant or in a homozygote, 1 point when phase is unknown, with supporting, moderate, strong, and very strong levels at 1, 2, 4, and 8 points respectively. The available case evidence documents only the single queried frameshift variant and does not document an affected Fanconi-anemia proband, a second pathogenic PALB2 variant, homozygosity, or confirmed trans/cis phase, so PM3 cannot be scored.

Rule
PALB2 PM3: Fanconi anemia phenotype with confirmed in-trans pathogenic variant or homozygosity earns 2 points; phase unknown earns 1 point; PM3 Supporting = 1 point, Moderate = 2 points, Strong = 4 points, Very Strong = 8 points.
Evidence considered
  • The PALB2 VCEP PM3 specification applies to Fanconi anemia and assigns 2 points for a phenotype-consistent proband with the variant confirmed in trans with a pathogenic variant or in a homozygote, 1 point when phase is unknown, and strength thresholds of 1, 2, 4, and 8 points.
  • The case evidence contains no affected Fanconi-anemia proband observation, no second pathogenic PALB2 allele, and no zygosity or phase result for the queried NM_024675.4:c.1049_1051delinsTTCT variant.
  • A review describes biallelic PALB2 mutations as causing Fanconi anemia type N, but it does not mention the queried variant or provide a case observation, genotype, or phase result for it.
  • A PALB2 cancer cohort paper describes biallelic inactivating PALB2 mutations as causing Fanconi anemia type N, but it does not report the queried variant or an applicable affected-proband observation.
Still missing
  • Affected-proband phenotype consistent with PALB2-related Fanconi anemia is not documented.
  • A second pathogenic or likely pathogenic PALB2 variant is not documented.
  • Zygosity and phase, specifically confirmed trans or homozygous status, are not documented.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3PMID:28858227 ↗PMID:28279176 ↗
PP1 Not assessed: no affected-relative segregation data, meioses, LOD, or Bayes factor were available to meet the PP1 threshold of LOD ≥0.3 or LR ≥2:1. Details ▾Hide ▴
Reasoning

PP1 is applicable under the PALB2 VCEP. The specification requires quantitative cosegregation assessment: supporting at LOD ≥0.3 or Bayes factor (LR) ≥2:1, moderate at LOD ≥0.60 or LR ≥4:1, and strong at LOD ≥1.26 or LR ≥18:1. The available case evidence contains no affected-relative segregation data, meioses, pedigree, LOD, or Bayes-factor calculation for this variant, so PP1 cannot be assigned.

Rule
PALB2 VCEP v1.3 PP1: supporting LOD ≥0.3 or LR ≥2:1; moderate LOD ≥0.60 or LR ≥4:1; strong LOD ≥1.26 or LR ≥18:1.
Evidence considered
  • The PALB2 VCEP requires quantitative cosegregation analysis for PP1, with supporting evidence at LOD ≥0.3 or Bayes factor (LR) ≥2:1; no qualifying family segregation data or calculation were provided.
Still missing
  • Documented segregation of the variant in affected relatives and a quantitative LOD or Bayes-factor calculation are required.
Sources
cspec ↗
BS2 Not assessed: the PALB2 VCEP excludes population cohorts such as gnomAD for BS2, and no qualifying healthy-adult or homozygote observation is available. Details ▾Hide ▴
Reasoning

The PALB2 VCEP requires BS2 assessment using its Fanconi anemia BS2 point tables, but explicitly states not to use individuals in population-based cohorts such as gnomAD. The available evidence shows only absence from population databases and contains no qualifying healthy-adult or homozygote observations, so BS2 cannot be assessed.

Rule
Use PALB2 Fanconi anemia BS2 point tables; do not use individuals in population-based cohorts such as gnomAD; BS2 Strong requires >=4 points, BS2 Moderate requires 2 points, and BS2 Supporting requires 1 point.
Evidence considered
  • The PALB2 VCEP states: do not use BS2 for individuals in population-based cohorts such as gnomAD.
  • The available gnomAD records report the variant as absent and provide no qualifying individual-level healthy-status or homozygosity observation.
Still missing
  • No qualifying clinically evaluated healthy-adult or homozygote observation with the variant was available for the PALB2 BS2 point table.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS4 Not assessed: no affected relatives tested negative and no quantitative non-segregation result met the BS4 supporting threshold of LOD ≤−0.32 or LR ≤0.48. Details ▾Hide ▴
Reasoning

BS4 is applicable under the PALB2 VCEP for lack of segregation in affected family members, but the specification cautions that phenocopies and multiple pathogenic variants can confound this interpretation. The available case evidence contains no affected relatives who tested negative, no non-segregation observations, no pedigree, and no LOD or Bayes-factor calculation. BS4 therefore cannot be assigned at any strength.

Rule
PALB2 VCEP v1.3 BS4: supporting LOD ≤−0.32 or LR ≤0.48; moderate LOD ≤−0.64 or LR ≤0.23; strong LOD ≤−1.28 or LR ≤0.053:1.
Evidence considered
  • The PALB2 VCEP defines BS4 supporting at LOD ≤−0.32 or Bayes factor (LR) ≤0.48 and warns that phenocopies or multiple pathogenic variants can mimic lack of segregation; no qualifying non-segregation data were provided.
Still missing
  • Documented non-segregation in affected relatives, phenotype assessment, exclusion of phenocopies or alternate pathogenic variants, and a quantitative LOD or Bayes-factor calculation are required.
Sources
cspec ↗
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the PALB2 PS1 specification is for matched splicing effects, whereas this variant is a Q350 frameshift. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PS1 through its splicing table. This variant is a frameshift, NP_078951.2:p.(Q350Lfs*11), rather than a splice variant or missense substitution, so the PS1 splicing rule does not apply.

Rule
Use PALB2 PS1 Splicing table; not applicable to this frameshift consequence.
Evidence considered
  • The PALB2 VCEP framework defines PS1 using the PALB2 PS1 Splicing table and requires comparison of predicted splicing events.
  • The case variant is NM_024675.4:c.1049_1051delinsTTCT with protein consequence NP_078951.2:p.(Q350Lfs*11), a frameshift rather than a splice-site substitution.
Sources
cspec ↗vcep_palb2_ps1_1_3
PS2 VCEPNot applicable: PALB2 VCEP version 1.3 explicitly designates PS2 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen PALB2 Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.3, explicitly designates PS2 as not applicable. Therefore, no de novo evidence is assessed under PS2 for this variant.

VCEP rule
PALB2 VCEP v1.3: PS2 not applicable.
Evidence considered
  • The PALB2 VCEP version 1.3 specification lists PS2 as not applicable.
Sources
cspec ↗
PS3 VCEPNot applicable: PALB2 VCEP Version 1.3 excludes PS3, and no validated assay directly tested c.1049_1051delinsTTCT or p.(Gln350LeufsTer11). Details ▾Hide ▴
Reasoning

The governing ClinGen PALB2 VCEP Version 1.3 specification explicitly designates PS3 as not applicable, so PS3 cannot be assigned to this frameshift variant. The reviewed variant-specific literature packet contains no report of a validated functional assay for NM_024675.4:c.1049_1051delinsTTCT or p.(Gln350LeufsTer11); general descriptions of PALB2 loss of function do not substitute for direct assay evidence.

VCEP rule
PALB2 VCEP Version 1.3: PS3 not applicable.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification lists PS3 as not applicable and provides no PS3 strength assignment rule.
  • The extracted full-text reviews and cohort reports did not mention c.1049_1051delinsTTCT or p.(Gln350LeufsTer11) and did not provide direct functional testing of this variant.
  • General PALB2 loss-of-function biology and studies of other truncating variants were not treated as direct PS3 evidence for this variant.
Still missing
  • No variant-specific validated protein or RNA functional assay was identified, although PS3 is excluded by the governing VCEP specification.
Sources
cspec ↗PMID:18053174 ↗PMID:25529982 ↗PMID:28279176 ↗PMID:28779002 ↗PMID:28858227 ↗
PM1 VCEPNot applicable: the PALB2 VCEP marks PM1 not applicable, and the variant is a Q350 truncating frameshift rather than a missense domain change. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP explicitly marks PM1 as not applicable. The variant is also a truncating frameshift at Q350 rather than a missense change for which a critical functional domain or hotspot would be evaluated. The authoritative vcep_materials.json domain_tables object is empty.

VCEP rule
PALB2 VCEP PM1 applicability: Not Applicable.
Evidence considered
  • The PALB2 VCEP criteria list PM1 as Not Applicable.
  • The authoritative domain_tables entry for PALB2 is empty, and the variant consequence is p.(Q350Lfs*11), a frameshift.
Sources
cspec ↗
PM4 VCEPNot applicable: PALB2 VCEP PM4 is restricted to stop-loss variants, whereas this variant is a frameshift producing p.(Q350Lfs*11). Details ▾Hide ▴
Reasoning

PM4 is not applicable under the PALB2 VCEP Version 1.3 specification. That specification restricts PM4 to stop-loss variants and does not use it for this frameshift consequence; the variant is not an in-frame insertion or deletion and does not remove a termination codon.

VCEP rule
PALB2 VCEP Version 1.3 PM4: use for stop-loss variants only
Evidence considered
  • PALB2 VCEP Version 1.3 states that PM4 is not applicable and should be used for stop-loss variants only.
  • The variant consequence is a frameshift, p.(Q350Lfs*11), not a stop-loss or in-frame length change.
Sources
cspec ↗
PM6 VCEPNot applicable: PALB2 VCEP version 1.3 explicitly designates PM6 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen PALB2 Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.3, explicitly designates PM6 as not applicable. Therefore, suspected de novo evidence without confirmed parental testing is not assessed under PM6 for this variant.

VCEP rule
PALB2 VCEP v1.3: PM6 not applicable.
Evidence considered
  • The PALB2 VCEP version 1.3 specification lists PM6 as not applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the PALB2 VCEP marks PP2 not applicable, and this variant is a truncating frameshift rather than missense. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP explicitly marks PP2 as not applicable. In addition, this variant is a truncating frameshift rather than a missense variant for which a gene-level missense mechanism would be considered.

VCEP rule
PALB2 VCEP PP2 applicability: Not Applicable.
Evidence considered
  • The PALB2 VCEP criteria list PP2 as Not Applicable.
  • The case variant has the frameshift consequence NP_078951.2:p.(Q350Lfs*11), not a missense consequence.
Sources
cspec ↗
PP3 N/ANot applicable: this is a frameshift variant, whereas PALB2 PP3 is specified for qualifying splice-impact variants rather than truncating variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11). The PALB2 VCEP specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants, not truncating frameshift variants; therefore no computational predictor was evaluated for PP3.

Rule
PALB2 VCEP PP3 scope: predicted splicing impact for silent, missense/in-frame, and qualifying intronic variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification limits PP3 to predicted splice impact for silent, missense/in-frame, and qualifying intronic variants; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗
PP4 VCEPNot applicable: the PALB2 VCEP prohibits PP4 for hereditary breast cancer because its phenotype is genetically heterogeneous. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PP4 as not applicable: it says not to use PP4 for autosomal-dominant disease because breast cancer has genetic heterogeneity and no features readily distinguish hereditary from sporadic causes; for autosomal-recessive disease, phenotype considerations are handled with PM3. This variant is being evaluated in the PALB2-related cancer-predisposition context, and no PP4 assignment is permitted by the governing specification.

VCEP rule
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. For AR disorder, use PM3 for specific phenotype considerations.
Evidence considered
  • PALB2 VCEP Version 1.3 PP4 instruction: "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. For AR disorder, use PM3 for specific phenotype considerations."
Sources
cspec ↗
PP5 VCEPNot applicable: the PALB2 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PP5 as not applicable and instructs that this criterion is not for use. In addition, the exact variant is reported as absent from ClinVar, so there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification that could satisfy the requested PP5 gate.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • PALB2 VCEP Version 1.3 PP5 instruction: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
  • ClinVar search returned no result for PALB2 NM_024675.4:c.1049_1051delinsTTCT; therefore no exact-variant expert-panel Pathogenic or Likely pathogenic assertion exists in the available evidence.
Sources
cspec ↗clinvar ↗
BS3 VCEPNot applicable: PALB2 VCEP Version 1.3 excludes BS3, and no validated benign assay result exists for c.1049_1051delinsTTCT or p.(Gln350LeufsTer11). Details ▾Hide ▴
Reasoning

The governing ClinGen PALB2 VCEP Version 1.3 specification explicitly designates BS3 as not applicable, so BS3 cannot be assigned to this frameshift variant. No reviewed source reports a validated benign functional result for NM_024675.4:c.1049_1051delinsTTCT or p.(Gln350LeufsTer11); absence of direct testing cannot establish a normal protein or splicing effect.

VCEP rule
PALB2 VCEP Version 1.3: BS3 not applicable.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification lists BS3 as not applicable and provides no BS3 strength assignment rule.
  • The extracted full-text reviews and cohort reports did not mention c.1049_1051delinsTTCT or p.(Gln350LeufsTer11) and did not provide direct functional testing of this variant.
  • Studies of other PALB2 truncating variants and gene-level biology were not treated as direct BS3 evidence for this variant.
Still missing
  • No variant-specific validated benign protein or RNA functional assay was identified, although BS3 is excluded by the governing VCEP specification.
Sources
cspec ↗PMID:18053174 ↗PMID:25529982 ↗PMID:28279176 ↗PMID:28779002 ↗PMID:28858227 ↗
BP1 N/ANot applicable: PALB2 BP1 is limited to missense variants, while this variant is a Q350 frameshift. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP1 rule applies to all missense variants. This variant is a truncating frameshift, NP_078951.2:p.(Q350Lfs*11), so BP1 does not apply.

Rule
BP1 supporting: apply to all missense variants; not applicable to this frameshift.
Evidence considered
  • The PALB2 VCEP BP1 rule states: Apply to all missense variants.
  • The case variant is a frameshift, NP_078951.2:p.(Q350Lfs*11), not a missense variant.
Sources
cspec ↗
BP2 VCEPNot applicable: the governing PALB2 VCEP specification explicitly designates BP2 as not applicable. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP framework explicitly lists BP2 as not applicable. Therefore, BP2 is not evaluated for this variant under the applicable gene-specific specification, regardless of whether any nearby or same-sample variant observations are available.

VCEP rule
PALB2 VCEP BP2: Not Applicable.
Evidence considered
  • The PALB2 ClinGen Expert Panel specification lists BP2 with applicability marked Not Applicable.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3
BP3 VCEPNot applicable: PALB2 VCEP marks BP3 unavailable, and this variant is a frameshift rather than an in-frame repeat-region length change. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the PALB2 VCEP Version 1.3 specification. The VCEP marks BP3 as not applicable, and this variant is a frameshift rather than an in-frame insertion or deletion in a repeat region.

VCEP rule
PALB2 VCEP Version 1.3 BP3: not applicable
Evidence considered
  • PALB2 VCEP Version 1.3 explicitly marks BP3 as not applicable.
  • The normalized consequence is a frameshift producing p.(Q350Lfs*11), not an in-frame insertion or deletion in a repetitive region.
Sources
cspec ↗
BP4 N/ANot applicable: this is a frameshift variant, outside the PALB2 BP4 scope for absence of predicted splicing impact. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11). The PALB2 VCEP specifies BP4 for no predicted splicing impact in splicing variants and explicitly excludes missense variants; truncating frameshift variants are outside the criterion scope, so no splice or other predictor was evaluated for BP4.

Rule
PALB2 VCEP BP4 scope: no predicted splicing impact via SpliceAI for splicing variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP specifies BP4 for no predicted splicing impact in splicing variants and excludes variants outside that scope; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants do not reliably explain phenotype differences. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies BP5 as not applicable and instructs not to use it because multiple pathogenic variants can occur without a noticeable phenotype difference, and PALB2 has moderate penetrance with more frequent co-occurrence of other pathogenic variants. No BP5 assignment is permitted under the governing PALB2 specification.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • PALB2 VCEP Version 1.3 BP5 instruction: "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype ... PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently."
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel classification. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies BP6 as not applicable and instructs that this criterion is not for use. Independently, the exact variant is absent from ClinVar, so there is no exact-variant ClinVar expert-panel Benign or Likely benign classification that could satisfy the requested BP6 gate.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • PALB2 VCEP Version 1.3 BP6 instruction: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
  • ClinVar search returned no result for PALB2 NM_024675.4:c.1049_1051delinsTTCT; therefore no exact-variant expert-panel Benign or Likely benign assertion exists in the available evidence.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant eligible for PALB2 BP7. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11), not a synonymous variant. The PALB2 VCEP limits BP7 to synonymous and qualifying deep intronic variants, so BP7 was not evaluated.

Rule
PALB2 VCEP BP7 scope: synonymous and qualifying deep intronic variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP limits BP7 to synonymous and qualifying deep intronic variants; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.1049_1051delinsTTCT
Protein (HGVS p.)
NP_078951.2:p.(Gln350LeufsTer11)
GRCh38
chr16:23635495 TTT>AGAA
GRCh37
chr16:23646816 TTT>AGAA
Location and type
Exon 4 · frameshift

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…
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

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -124 bp
0.001
SpliceAI acceptor gainat -361 bp
0.000
SpliceAI donor lossat -63 bp
0.001
SpliceAI donor gainat +246 bp
0.013
Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.019

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: this is a frameshift variant, whereas PALB2 PP3 is specified for qualifying splice-impact variants rather than truncating variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11). The PALB2 VCEP specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants, not truncating frameshift variants; therefore no computational predictor was evaluated for PP3.

Rule
PALB2 VCEP PP3 scope: predicted splicing impact for silent, missense/in-frame, and qualifying intronic variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification limits PP3 to predicted splice impact for silent, missense/in-frame, and qualifying intronic variants; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗
BP4 N/ANot applicable: this is a frameshift variant, outside the PALB2 BP4 scope for absence of predicted splicing impact. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11). The PALB2 VCEP specifies BP4 for no predicted splicing impact in splicing variants and explicitly excludes missense variants; truncating frameshift variants are outside the criterion scope, so no splice or other predictor was evaluated for BP4.

Rule
PALB2 VCEP BP4 scope: no predicted splicing impact via SpliceAI for splicing variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP specifies BP4 for no predicted splicing impact in splicing variants and excludes variants outside that scope; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗
BP7 N/ANot applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant eligible for PALB2 BP7. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.1049_1051delinsTTCT is a frameshift variant, p.(Gln350LeufsTer11), not a synonymous variant. The PALB2 VCEP limits BP7 to synonymous and qualifying deep intronic variants, so BP7 was not evaluated.

Rule
PALB2 VCEP BP7 scope: synonymous and qualifying deep intronic variants; not applicable to frameshift variants.
Evidence considered
  • The PALB2 Version 1.3 VCEP limits BP7 to synonymous and qualifying deep intronic variants; this case is a frameshift variant, p.(Gln350LeufsTer11).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

5 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

  • Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
    This paper reports a different truncating PALB2 variant, c.2323C>T (p.Q775X), in French-Canadian breast-cancer cases; it does not report the variant under review or a functional assay of it.
    Does not name this variant
    PMID 18053174 ↗
    Quoted passage
    This mutation is clearly pathogenic as it truncates the protein, and other truncating mutations occurring both before and after this amino acid are known to be capable of causing breast cancer.

    Results, second paragraph; Table 2

  • A novel PALB2 truncating mutation in an Italian family with male breast cancer.
    This paper reports a different PALB2 truncating variant, c.1285_1286delAinsTC (p.I429SfsX12), in a hereditary breast-cancer family; it does not report the variant under review or a functional assay of it.
    Does not name this variant
    PMID 25529982 ↗
    Quoted passage
    The novel mutation c.1285_1286delAinsTC (p.I429SfsX12) was found to be localized in exon 4 of PALB2, in the region that encodes for the ChAM motif.

    Discussion, page 1246; Results, page 1244; Table I

  • PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
    This paper describes PALB2 biology and reports other truncating mutations in cancer patients, but it does not report c.1049_1051delinsTTCT or p.(Q350Lfs*11) and provides no functional assay of the queried variant.
    Does not name this variant
    PMID 28279176 ↗
    Quoted passage
    The PALB2 protein interacts with both BRCA1 and BRCA2 through its N-terminal coiled-coil and C-terminal WD-40 domains, respectively.

    Background, paragraphs 2–3; Results, NGS analysis

  • Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
    This population-based study analyzes PALB2 protein-truncating variants in aggregate and reports increased breast-cancer risk, but it does not mention c.1049_1051delinsTTCT or p.(Q350Lfs*11) and does not provide a functional assay of the queried variant.
    Does not name this variant
    PMID 28779002 ↗
    Quoted passage
    Of the four genes, truncating variants in PALB2 were associated with the highest BC risk, with an estimated OR=4.69 (95% CI 2.27 to 9.68, p=6.9×10−6).

    Results, ‘BC risks associated with ATM, CHEK2 and PALB2 truncating variants’

  • The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
    This review describes PALB2 as a component of homologous-recombination and Fanconi-anemia DNA-repair pathways, but it does not mention c.1049_1051delinsTTCT or p.(Q350Lfs*11) and provides no variant-specific functional assay.
    Does not name this variant
    PMID 28858227 ↗
    Quoted passage
    PALB2 is a pivotal player of the DNA damage repair; especially by its participation on the Fanconi anemia (FA) pathway; biallelic PALB2 mutations cause the N subtype of Fanconi anemia (FA-N).

    Introduction, final paragraph

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 0.013 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

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

Not available in gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.