Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic 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.
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.
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.
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.3, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 3 not assessed · 19 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Only the requested codon/residue/domain criteria were assessed.
The PALB2 VCEP framework governs this case and explicitly makes PS1, PM1, PP2, and BP1 inapplicable for this variant or criterion context; its truncation-specific PM5_supporting rule is met by the observed NMD-prone frameshift terminating at codon 360, upstream of p.His1184.
PS2 and PM6 are excluded by the governing PALB2 VCEP; PP1 and BS4 cannot be assigned without the VCEP-mandated quantitative co-segregation result.
Within this group, PS4 is not met because the exact-variant case-control observation is not statistically significant under the PALB2 VCEP threshold; PP4, PP5, BP5, and BP6 are not applicable under the governing PALB2 specification and/or the requested evidence gates.
All three requested criteria are not applicable because the variant is a frameshift, an upstream scope exclusion for PP3, BP4, and BP7.
The governing PALB2 VCEP Version 1.3 framework was used in preference to generic ACMG defaults.
Population evidence supports PM2 at supporting strength because the variant is absent from both available all-comers gnomAD datasets.
No population frequency supports BA1 or BS1, and the available data do not establish the PALB2 point-based BS2 observations.
No criteria match.
Met · 3
PVS1Very strongMet at very strong: frameshift p.(Q350Hfs*11) in exon 4 truncates PALB2 after 349 native residues and is far upstream of the extreme 3-prime region.
Details ▾Hide ▴
Reasoning
PVS1 is met at very strong strength. The PALB2 VCEP Version 1.3 specification recognizes frameshift variants as null variants eligible for PVS1 and establishes PALB2 loss of function as a disease mechanism. NM_024675.4 is the relevant PALB2 coding transcript corresponding to the VCEP default NM_024675.3 annotation, and the variant produces p.(Gln350HisfsTer11) / p.(Q350Hfs*11), an early truncation in coding exon 4 that retains only 349 native PALB2 residues. This position is far from the extreme 3-prime end and is expected to be NMD-prone; the PALB2-specific caution for extreme 3-prime truncations or splice events leaving the remainder of the protein intact does not apply. The exact variant was independently reported as a truncating frameshift in exon 4. No named PALB2 VCEP or ClinGen SVI downgrade rule is triggered, so the full strength is very strong.
Rule
PALB2 VCEP Version 1.3 PVS1 null-variant guidance, interpreted with the ClinGen SVI PVS1 framework; no downgrade rule applies.
Evidence considered
The PALB2 VCEP Version 1.3 PVS1 specification identifies null variants, including frameshift variants, as eligible for PVS1 when loss of function is an established disease mechanism.
The case variant is NM_024675.4:c.1050_1051delinsTCT, predicted to produce p.(Gln350HisfsTer11) / p.(Q350Hfs*11), an early truncation rather than an extreme 3-prime truncation.
The exact variant was reported as a heterozygous truncating frameshift in exon 4 and described as retaining only 349 residues of native PALB2 (PMID:18446436).
The ClinGen SVI PVS1 framework supports full-strength PVS1 for a truncating variant when the relevant transcript and loss-of-function mechanism are established and no NMD-escape or non-critical-region downgrade applies.
PM2SupportingMet at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying PALB2's ≤0.000333% PM2 threshold.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP specifies PM2 at supporting strength when the variant frequency is at or below 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with a one-carrier single-subpopulation exception. The variant is absent from gnomAD v2.1 and gnomAD v4.1, satisfying this rarity requirement. The governing specification does not require a non-cancer-only or exome-only subset for PM2.
Rule
Frequency ≤1/300,000 (0.000333%) in gnomAD subpopulation with the highest frequency; PM2 supporting
Evidence considered
The PALB2 Version 1.3 specification defines PM2 supporting as frequency ≤1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with an exception for one carrier confined to a single subpopulation.
The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, which is below the specified PM2 frequency threshold.
PM5SupportingMet at supporting: the observed p.Gln350HisfsTer11 frameshift terminates at codon 360, upstream of the PALB2 VCEP PM5 cutoff p.His1184.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP v1.3 expands PM5_supporting beyond classic same-residue missense comparisons: it applies to all NMD-prone DNA truncating variants receiving PVS1 at Very Strong strength when the premature termination codon is upstream of p.His1184. NM_024675.4:c.1050_1051delinsTCT is an observed frameshift producing p.(Gln350HisfsTer11), with the premature termination codon at codon 360, well upstream of p.His1184. The variant is directly reported as the truncating frameshift 1050_1051delAAinsTCT in a breast-cancer family, supporting that this is an observed DNA truncating variant. The available variant assessment identifies frameshift consequence and a suggested PVS1 Very Strong default; under the VCEP rule, PM5_supporting is met.
Rule
PALB2 VCEP PM5_supporting: apply to all NMD-prone DNA truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.
Evidence considered
PALB2 VCEP v1.3 PM5_supporting applies to NMD-prone DNA truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.
The case variant is a frameshift, p.(Gln350HisfsTer11), placing the premature termination at codon 360, upstream of p.His1184.
PMID:18446436 directly reports the same truncating frameshift as 1050_1051delAAinsTCT in a breast-cancer family.
PS4Not met: the exact variant occurred in 1/360 cases versus 0/864 controls, with two-sided exact p=1.0 rather than the VCEP PS4 threshold of ≤.05.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP specifies PS4 Strong for a case-control study with p-value ≤.05 and either odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5. PMID:18446436 reports this exact variant in 1 of 360 BRCA1/BRCA2-negative Chinese women with early-onset or familial breast cancer and in 0 of 864 unaffected controls. The available counts do not provide a qualifying statistically significant enrichment: with one total carrier across the two groups, the two-sided exact comparison is p=1.0, and no confidence interval meeting the VCEP requirement is reported. Therefore PS4 is not met.
Rule
Case-control studies; p-value ≤.05 and (Odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5).
Evidence considered
The PALB2 VCEP PS4 rule states: "Case-control studies; p-value ≤.05 and (Odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5)."
PMID:18446436 reports the exact PALB2 1050_1051delAAinsTCT variant in 1 of 360 affected women and its absence in 864 unaffected controls.
Using those reported counts, the two-sided exact case-control comparison is p=1.0; the explicit VCEP comparison is p=1.0 ≤ .05? no.
Still missing
No reported odds ratio or confidence interval is available, but the observed single-carrier case-control counts already fail the required statistical significance threshold.
BA1Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.1% BA1 threshold.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP specifies BA1 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 observed allele frequency reaches the BA1 threshold. The governing specification does not require a non-cancer-only or exome-only subset for this rule.
Rule
Grpmax Filtering AF >0.1% in gnomAD; Stand Alone
Evidence considered
The PALB2 Version 1.3 specification defines BA1 as group maximum filtering allele frequency >0.1% in gnomAD.
The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; therefore, there is no frequency meeting the BA1 threshold.
BS1Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds PALB2's >0.01% BS1 threshold.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP specifies BS1 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 observed allele frequency reaches the BS1 threshold. The governing specification does not require a non-cancer-only or exome-only subset for this rule.
Rule
Grpmax Filtering AF >0.01% in gnomAD; Strong
Evidence considered
The PALB2 Version 1.3 specification defines BS1 as group maximum filtering allele frequency >0.01% in gnomAD.
The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; therefore, there is no frequency meeting the BS1 threshold.
PP1Not assessed: one affected mother segregated the variant with the proband, but no required quantitative result was provided to compare with LOD ≥0.3 or LR ≥2:1.
Details ▾Hide ▴
Reasoning
The exact variant was reported in one affected proband and her affected mother, supporting familial transmission and phenotype consistency. However, the PALB2 VCEP mandates quantitative co-segregation analysis for PALB2 alterations, and no LOD score or Bayes factor was provided. The available observation therefore cannot be assigned PP1 strength under the governing rule: supporting requires LOD ≥0.3 or LR ≥2:1, moderate requires LOD ≥0.60 or LR ≥4:1, and strong requires LOD ≥1.26 or LR ≥18:1.
Rule
PALB2 PP1 requires quantitative co-segregation; 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 mandates quantitative co-segregation analysis and defines PP1 supporting as LOD ≥0.3 or Bayes factor/LR ≥2:1, moderate as LOD ≥0.60 or LR ≥4:1, and strong as LOD ≥1.26 or LR ≥18:1.
The exact variant was reported in a family with breast cancer: the proband was diagnosed at age 44, her mother was diagnosed with breast cancer at the same age, and the mother carried the same variant.
The observed affected-relative segregation is relevant to PP1, but the report does not provide a quantitative LOD score or Bayes factor/LR.
Still missing
A quantitative PALB2 co-segregation analysis incorporating the proband, affected mother, phenotype, and available pedigree data is required.
The resulting LOD score or Bayes factor/LR is not available, so PP1 strength cannot be assigned.
BS2Not assessed: no documented homozygote or unaffected-carrier observations are available to meet PALB2's BS2 point thresholds.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP evaluates BS2 using point-based evidence from unaffected individuals and homozygotes, with supporting strength at 1 point, moderate at 2 points, and strong at at least 4 points. The available population records report the variant as absent rather than documenting homozygous individuals or unaffected carriers, so the required BS2 observations and points cannot be established.
Rule
BS2: supporting = 1 point, moderate = 2 points, strong = at least 4 points; see PALB2 Fanconi anemia BS2 tables
Evidence considered
The PALB2 Version 1.3 BS2 specification requires point-based evidence: 1 point for supporting, 2 points for moderate, and at least 4 points for strong.
gnomAD v2.1 and v4.1 report absence of the variant, but do not provide a documented homozygote or unaffected-carrier observation for BS2.
Still missing
Documented unaffected carriers or homozygous individuals with sufficient phenotype and inheritance context are needed to calculate PALB2 BS2 points.
BS4Not assessed: no non-segregation was reported, and no quantitative LOD or LR was provided to compare with the BS4 thresholds.
Details ▾Hide ▴
Reasoning
No affected-relative non-segregation or other family-level evidence contradicting inheritance of the variant was reported. The PALB2 VCEP requires quantitative co-segregation analysis for BS4, and no LOD score or Bayes factor was provided to test the thresholds for supporting, moderate, or strong BS4.
Rule
PALB2 BS4 requires quantitative co-segregation; 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 as LOD ≤−0.32 or LR ≤0.48, moderate as LOD ≤−0.64 or LR ≤0.23, and strong as LOD ≤−1.28 or LR ≤0.053:1, using quantitative co-segregation analysis.
The exact-variant report documents transmission from an affected mother to the affected proband, but does not report non-segregation in affected relatives or a quantitative LOD score/Bayes factor.
Still missing
A complete pedigree and quantitative co-segregation analysis are needed to evaluate non-segregation.
No LOD score or Bayes factor/LR is available for comparison with BS4 supporting LOD ≤−0.32 or LR ≤0.48, moderate LOD ≤−0.64 or LR ≤0.23, or strong LOD ≤−1.28 or LR ≤0.053:1.
Not applicable · 19· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: the variant is a p.Gln350HisfsTer11 frameshift, whereas PALB2 PS1 is restricted to matched splicing events in the VCEP table.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP PS1 specification is a splicing-table rule requiring comparison with a known pathogenic or likely pathogenic splice-altering event. This variant is an exonic frameshift, NM_024675.4:c.1050_1051delinsTCT, predicted to produce p.(Gln350HisfsTer11), not a splice-site substitution or an amino-acid substitution with an established same-event comparator. Therefore PS1 is not applicable.
Rule
PALB2 VCEP PS1 splicing table; prerequisite is a precisely matching predicted splice event.
Evidence considered
The PALB2 VCEP PS1 table defines PS1 by matching predicted splice events; this variant is annotated as a frameshift producing p.(Gln350HisfsTer11).
PS2VCEPNot applicable: the PALB2 VCEP explicitly excludes PS2 because informative de novo occurrences have not been established for this autosomal dominant cancer-predisposition condition.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP Version 1.3 explicitly designates PS2 as not applicable for autosomal dominant PALB2-related cancer predisposition because informative de novo occurrences have not been observed and sporadic breast cancer makes de novo evidence uninformative.
VCEP rule
PS2 is not applicable for PALB2 autosomal dominant disease under the Version 1.3 VCEP specification.
Evidence considered
The PALB2 VCEP Version 1.3 states that PS2 must not be used for autosomal dominant disease because informative de novo occurrences have not yet been observed and sporadic breast cancer is common.
PS3VCEPNot applicable: the PALB2 VCEP specification designates PS3 as unavailable for PALB2 variant classification.
Details ▾Hide ▴
Reasoning
The governing PALB2 VCEP specification explicitly designates PS3 as not applicable. Therefore, functional assay evidence cannot be used to assign PS3 for this variant under the applicable framework, regardless of the available truncating-variant or gene-level functional context.
VCEP rule
PS3 is not applicable under the PALB2 VCEP Version 1.3 specification.
Evidence considered
The PALB2 Version 1.3 VCEP specification lists PS3 as not applicable, so no PS3 strength can be assigned under the governing framework.
PM1VCEPNot applicable: the governing PALB2 VCEP explicitly marks PM1 as not applicable, and this variant is a truncating frameshift rather than missense.
Details ▾Hide ▴
Reasoning
The governing PALB2 VCEP framework explicitly marks PM1 as not applicable. The variant is also a truncating frameshift rather than a missense change for which a critical functional domain or hotspot would ordinarily be assessed. No separate applicable PALB2 PM1 domain rule is provided in the governing materials.
VCEP rule
PALB2 VCEP PM1 applicability: Not Applicable.
Evidence considered
The PALB2 VCEP criteria list marks PM1 as Not Applicable; the variant consequence is frameshift rather than missense.
PM3N/ANot applicable: PALB2 PM3 is restricted to recessive Fanconi anemia with biallelic evidence, but this variant is reported heterozygously without a pathogenic variant in trans.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP Version 1.3 specification defines PM3 for autosomal-recessive Fanconi anemia evidence, requiring a pathogenic or likely pathogenic variant in trans or homozygosity and assigning points according to affected-proband phenotype and phase. This case documents the queried frameshift as heterozygous in a breast-cancer family, inherited from the affected mother, with no reported second PALB2 pathogenic variant in trans, no homozygous state, and no Fanconi anemia phenotype. Therefore PM3 is not applicable to this PALB2-related cancer-predisposition interpretation; the published case observation does not establish the required biallelic phase evidence.
Rule
PALB2 VCEP Version 1.3 PM3: apply only for autosomal-recessive Fanconi anemia evidence using the Fanconi anemia PM3 point tables; PM3 Supporting = 1 point, Moderate = 2 points, Strong = >=4 points, and Very Strong = >=8 points.
Evidence considered
PALB2 VCEP Version 1.3 specifies PM3 for recessive Fanconi anemia and requires point assignment based on a confirmed-in-trans or homozygous pathogenic configuration, with phase-unknown configurations handled separately.
The exact variant 1050_1051delAAinsTCT was reported as a heterozygous truncating variant in a breast-cancer family; testing showed inheritance from the maternal side, with no second PALB2 pathogenic allele or Fanconi anemia phenotype reported.
Because the available observation is heterozygous and lacks demonstrated biallelic phase, it cannot satisfy the PALB2 PM3 Fanconi anemia framework.
PM4VCEPNot applicable: the PALB2 VCEP Version 1.3 specification explicitly designates PM4 as not applicable.
Details ▾Hide ▴
Reasoning
PM4 is not applicable under the PALB2 VCEP Version 1.3 specification. The variant is a frameshift null variant, and the governing PALB2 framework explicitly marks PM4 as not applicable; therefore generic ACMG PM4 reasoning is not used.
VCEP rule
PALB2 VCEP Version 1.3: PM4 not applicable.
Evidence considered
The PALB2 VCEP Version 1.3 criterion table explicitly lists PM4 as not applicable.
The variant consequence is a frameshift, but the governing gene-specific framework takes precedence over generic ACMG applicability.
PM6VCEPNot applicable: the PALB2 VCEP explicitly excludes PM6 for both autosomal dominant and recessive disease in its Version 1.3 framework.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP Version 1.3 explicitly designates PM6 as not applicable for both autosomal dominant and autosomal recessive disease; assumed de novo observations are not informative for this framework.
VCEP rule
PM6 is not applicable for PALB2 under the Version 1.3 VCEP specification.
Evidence considered
The PALB2 VCEP Version 1.3 states not to use PM6 for autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo recessive events are unlikely to be informative.
PP2VCEPNot applicable: PALB2 VCEP excludes PP2, and the variant is a p.Gln350HisfsTer11 frameshift rather than a missense variant.
Details ▾Hide ▴
Reasoning
The governing PALB2 VCEP explicitly marks PP2 as not applicable. In addition, PP2 is a missense-oriented criterion, while this variant is a frameshift, p.(Gln350HisfsTer11), so a gene-level missense mechanism assessment cannot be applied.
VCEP rule
PALB2 VCEP PP2 applicability: Not Applicable.
Evidence considered
The PALB2 VCEP criteria list marks PP2 as Not Applicable; the variant consequence is frameshift.
PP3N/ANot applicable: this is a frameshift variant, outside the PALB2 VCEP PP3 scope for missense, silent, and qualifying intronic/splicing variants.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), rather than a missense or splice-region/intronic variant. The PALB2 VCEP specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants, and excludes this frameshift scope; therefore SpliceAI, REVEL, and other computational scores were not evaluated for PP3.
Rule
PALB2 VCEP Version 1.3: PP3 applies to predicted splicing impact for silent, missense/in-frame, and qualifying intronic variants; this frameshift is outside scope.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants and does not include frameshift variants in this computational criterion's scope.
PP4VCEPNot applicable: the PALB2 VCEP excludes PP4 for autosomal dominant disease because breast cancer is genetically heterogeneous and not phenotype-specific.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP marks PP4 not applicable for autosomal dominant PALB2-related cancer predisposition because breast cancer has multiple genetic etiologies and no phenotype features readily distinguish hereditary from sporadic disease. The reported breast-cancer phenotype therefore cannot activate PP4 under 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.
Evidence considered
The PALB2 VCEP PP4 instruction states: "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."
PP5VCEPNot applicable: the exact ClinVar record has no expert-panel assertion, only one non-expert Pathogenic submission without assertion criteria.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP marks PP5 not applicable. Independently, the exact ClinVar record has one ordinary Leiden Open Variation Database submission, classified Pathogenic with no assertion criteria and no expert-panel submission. It therefore cannot trigger the requested exact-variant ClinVar expert-panel PP5 rule.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; requested exact-variant ClinVar expert-panel gate is not satisfied.
Evidence considered
The PALB2 VCEP states that PP5 is not applicable for this VCEP.
The exact ClinVar record contains one SCV001193059 Leiden Open Variation Database submission, classified Pathogenic, with review status "no assertion criteria provided"; expert-panel submissions: 0.
Under the requested rule, an ordinary laboratory or non-expert assertion cannot activate PP5.
BS3VCEPNot applicable: the PALB2 VCEP specification designates BS3 as unavailable for PALB2 variant classification.
Details ▾Hide ▴
Reasoning
The governing PALB2 VCEP specification explicitly designates BS3 as not applicable. Therefore, validated benign functional assay evidence cannot be used to assign BS3 for this variant under the applicable framework.
VCEP rule
BS3 is not applicable under the PALB2 VCEP Version 1.3 specification.
Evidence considered
The PALB2 Version 1.3 VCEP specification lists BS3 as not applicable, so no BS3 strength can be assigned under the governing framework.
BP1N/ANot applicable: BP1 is restricted to missense variants, while this variant produces the p.Gln350HisfsTer11 frameshift.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP BP1 rule applies to all missense variants. This variant is an exonic frameshift, NM_024675.4:c.1050_1051delinsTCT, producing p.(Gln350HisfsTer11), so the missense-specific benign criterion does not apply.
Rule
PALB2 VCEP BP1: apply to all missense variants.
Evidence considered
The PALB2 VCEP BP1 rule states Apply to all missense variants; this variant is annotated as a frameshift.
BP2VCEPNot applicable: the PALB2 VCEP excludes BP2, and the case reports no pathogenic variant in cis or in trans with this heterozygous frameshift.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP Version 1.3 specification marks BP2 as not applicable and provides no PALB2 BP2 strength rule. The exact-variant report describes a heterozygous inherited frameshift in a breast-cancer family but does not document a pathogenic variant in cis or in trans. Accordingly, BP2 cannot be assigned under the governing PALB2 framework.
VCEP rule
PALB2 VCEP Version 1.3: BP2 not applicable.
Evidence considered
PALB2 VCEP Version 1.3 lists BP2 as not applicable and supplies no assignable BP2 strength rule for PALB2.
The exact-variant publication reports a heterozygous maternally inherited frameshift but does not report another pathogenic variant in cis or in trans.
The explicit PALB2 VCEP exclusion controls over the generic BP2 definition.
BP3VCEPNot applicable: BP3 is explicitly not applicable in PALB2 VCEP Version 1.3 and this variant is a truncating frameshift, not an in-frame repeat-region indel.
Details ▾Hide ▴
Reasoning
BP3 is not applicable under the PALB2 VCEP Version 1.3 specification. The variant is a protein-truncating frameshift rather than an in-frame deletion or insertion in a repetitive region, and the governing PALB2 framework explicitly marks BP3 as not applicable.
VCEP rule
PALB2 VCEP Version 1.3: BP3 not applicable.
Evidence considered
The PALB2 VCEP Version 1.3 criterion table explicitly lists BP3 as not applicable.
The case variant is a frameshift producing p.(Q350Hfs*11), not an in-frame insertion or deletion for which repeat-region BP3 could be considered.
BP4N/ANot applicable: this is a frameshift variant, outside the PALB2 VCEP BP4 scope for predicted splice impact in qualifying splicing variants.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), not a missense or splice-region/intronic variant. The PALB2 VCEP limits BP4 to no predicted splicing impact for splicing variants and explicitly excludes missense variants; a frameshift is outside this criterion's scope, so SpliceAI, REVEL, and other computational scores were not evaluated for BP4.
Rule
PALB2 VCEP Version 1.3: BP4 applies to no predicted splicing impact for qualifying splicing variants and is not applied to out-of-scope frameshift variants.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule limits BP4 to no predicted splicing impact for splicing variants and states that it should not be applied to missense variants; frameshift variants are outside the specified scope.
BP5VCEPNot applicable: the PALB2 VCEP explicitly excludes BP5 because PALB2 moderate penetrance and multiple pathogenic variants make co-occurrence non-informative.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP marks BP5 not applicable and explicitly instructs users not to use it because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2 has moderate penetrance. No alternate molecular basis is established for this case in the available evidence.
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.
Evidence considered
The PALB2 VCEP BP5 instruction states: "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype ... PALB2 has moderate penetrance ..."
BP6VCEPNot applicable: the exact ClinVar record has no benign expert-panel classification and instead has one non-expert Pathogenic submission without criteria.
Details ▾Hide ▴
Reasoning
The PALB2 VCEP marks BP6 not applicable. The exact ClinVar record contains no benign or likely benign expert-panel classification; it contains one non-expert Pathogenic submission without assertion criteria. Thus BP6 is not triggered under either the governing VCEP or the requested expert-panel-only rule.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; requested exact-variant ClinVar expert-panel benign/likely benign gate is not satisfied.
Evidence considered
The PALB2 VCEP states that BP6 is not applicable for this VCEP.
The exact ClinVar record reports zero expert-panel submissions and one Leiden Open Variation Database Pathogenic submission with no assertion criteria.
Under the requested rule, only an exact-variant ClinVar expert-panel Benign or Likely benign classification could trigger BP6; that evidence is absent.
BP7N/ANot applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant covered by the PALB2 VCEP BP7 rule.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), not a synonymous or deep intronic variant. The PALB2 VCEP specifies BP7 for synonymous and qualifying deep intronic variants, with RNA-based BP7 reserved for observed absence of an aberrant RNA defect; neither scope applies here.
Rule
PALB2 VCEP Version 1.3: BP7 applies to synonymous and qualifying deep intronic variants, not frameshift variants.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule specifies BP7 for synonymous and qualifying deep intronic variants, including an RNA-based form when an aberrant RNA defect is absent; this frameshift is outside scope.
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PALB2—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele 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
0.012
Pangolin splice lossmagnitude shown
-0.005
Pangolin splice gain
0.017
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: this is a frameshift variant, outside the PALB2 VCEP PP3 scope for missense, silent, and qualifying intronic/splicing variants.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), rather than a missense or splice-region/intronic variant. The PALB2 VCEP specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants, and excludes this frameshift scope; therefore SpliceAI, REVEL, and other computational scores were not evaluated for PP3.
Rule
PALB2 VCEP Version 1.3: PP3 applies to predicted splicing impact for silent, missense/in-frame, and qualifying intronic variants; this frameshift is outside scope.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule specifies PP3 for predicted splicing impact in silent, missense/in-frame, and qualifying intronic variants and does not include frameshift variants in this computational criterion's scope.
BP4N/ANot applicable: this is a frameshift variant, outside the PALB2 VCEP BP4 scope for predicted splice impact in qualifying splicing variants.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), not a missense or splice-region/intronic variant. The PALB2 VCEP limits BP4 to no predicted splicing impact for splicing variants and explicitly excludes missense variants; a frameshift is outside this criterion's scope, so SpliceAI, REVEL, and other computational scores were not evaluated for BP4.
Rule
PALB2 VCEP Version 1.3: BP4 applies to no predicted splicing impact for qualifying splicing variants and is not applied to out-of-scope frameshift variants.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule limits BP4 to no predicted splicing impact for splicing variants and states that it should not be applied to missense variants; frameshift variants are outside the specified scope.
BP7N/ANot applicable: this is a frameshift variant, not a synonymous or qualifying deep intronic variant covered by the PALB2 VCEP BP7 rule.
Details ▾Hide ▴
Reasoning
Not applicable because NM_024675.4:c.1050_1051delinsTCT is a frameshift variant, predicted as p.(Gln350HisfsTer11), not a synonymous or deep intronic variant. The PALB2 VCEP specifies BP7 for synonymous and qualifying deep intronic variants, with RNA-based BP7 reserved for observed absence of an aberrant RNA defect; neither scope applies here.
Rule
PALB2 VCEP Version 1.3: BP7 applies to synonymous and qualifying deep intronic variants, not frameshift variants.
Evidence considered
The case consequence assessment identifies NM_024675.4:c.1050_1051delinsTCT as a frameshift producing p.(Gln350HisfsTer11).
The PALB2 VCEP Version 1.3 rule specifies BP7 for synonymous and qualifying deep intronic variants, including an RNA-based form when an aberrant RNA defect is absent; this frameshift is outside scope.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
8 paper records listed. 1 cited in the classification.
Cited in the classification
The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives.
Cao AY et al. · 2009 Apr
This paper explicitly reports the same PALB2 variant as 1050_1051delAAinsTCT, a heterozygous truncating frameshift in exon 4 that produces a Q350 frameshift/fusion protein retaining only 349 residues of native PALB2. It was identified in one of 360 BRCA1/BRCA2-negative Chinese women with early-onset or familial breast cancer and was absent in 864 unaffected controls.
→ PVS1 · very strong→ PM5 · supportingNames this variant
A frameshift mutation, 1050_1051delAAinsTCT, was detected in a family with breast cancer history, the genetic testing about the proband’s mother indicated that this mutation was inherited from the maternal side.
Location Results, Clinical features of mutation carriers; Discussion; Tables 1–3; Fig. 2
Context PALB2 mutation screening by PCR-DHPLC followed by bidirectional Sanger sequencing in 360 BRCA1/BRCA2-negative Chinese women with early-onset or familial breast cancer; comparison with 864 unaffected controls and family-member testing.
Other recorded publications
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.