PALB2 c.1049_1050insT, p.(Gln350HisfsTer11)

Reasoning

NM_024675.4:c.1049_1050insT is a frameshift producing NP_078951.2:p.(Q350Hfs*11), with a premature termination codon at approximately p.360 in the PALB2 coding sequence. PALB2 loss of function is an established disease mechanism, and the PALB2 VCEP specifies PVS1 for null variants while cautioning mainly for extreme 3-prime truncations or splice events that preserve the remainder of the protein. This early coding frameshift is on the VCEP default RefSeq transcript (NM_024675.3; the case uses the compatible .4 record), is not a canonical splice variant, and is far upstream of the VCEP p.His1184 cutoff; no evidence indicates NMD escape, a non-critical exon, or a repeat-region exception. The generic ClinGen SVI PVS1 framework therefore supports the default, full-strength call without a downgrade.

Rule

PALB2 VCEP PVS1 decision tree with generic ClinGen SVI PVS1 framework; no downgrade applies

Evidence considered

• The PALB2 VCEP Version 1.3 identifies nonsense and frameshift variants as PVS1-eligible null variants when PALB2 loss of function is a known disease mechanism, with caution for extreme 3-prime truncations and splice events that leave the remainder of the protein intact.
• The VCEP materials specify NM_024675.3/ENST00000261584.8 as the default RefSeq transcript; NM_024675.4 is the compatible version used for this case and yields p.(Q350Hfs*11).
• The variant assessment gives a frameshift consequence and p.(Q350Hfs*11), placing the predicted premature termination around residue 360, well upstream of the PALB2 VCEP p.His1184 cutoff.
• The ClinGen SVI PVS1 framework supports full-strength PVS1 for a loss-of-function frameshift when no applicable NMD-escape, non-critical-region, transcript-relevance, or other downgrade is established.

Sources

Reasoning

The PALB2 VCEP Version 1.3 specifies PM2 at supporting strength when the variant frequency is at most 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with an exception allowing a single observation confined to one subpopulation. The variant is absent from gnomAD v2.1 and v4.1, and also absent from the available gnomAD v2.1 and v3.1 non-cancer subsets. Thus the observed allele frequency is zero in every evaluated source and is below the PM2 threshold; the single-observation exception is not needed.

Rule

Frequency <=1/300,000 (0.000333%) in gnomAD subpopulation with the highest frequency; exception for >0.000333% when n=1 in one subpopulation only

Evidence considered

• PALB2 VCEP Version 1.3 specifies PM2 supporting for frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; it also permits a single observation confined to one subpopulation.
• The variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to observed frequency 0 in those datasets.
• The variant is absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets as well.

Sources

Reasoning

PM5 is met at supporting strength under the PALB2 VCEP truncation-specific rule. The rule applies to NMD-prone truncating variants that receive PVS1 at Very Strong strength and introduce a premature termination codon upstream of p.His1184. This variant is a frameshift producing p.(Gln350HisfsTer11), with the premature termination codon at approximately His360, well upstream of His1184; PALB2 loss of function is an established disease mechanism in the VCEP framework and the variant-level assessment identifies a frameshift with a suggested PVS1 Very Strong assessment. No same-residue missense comparator is required because PALB2's governing PM5 rule is truncation-specific rather than classic same-residue missense PM5.

Rule

PM5 Supporting: apply to NMD-prone truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.

Evidence considered

• The PALB2 VCEP PM5 rule applies at supporting strength to NMD-prone truncating variants receiving PVS1 at Very Strong strength with premature termination codons upstream of p.His1184.
• The variant-level consequence is a frameshift, NP_078951.2:p.(Gln350HisfsTer11), placing the premature termination codon near His360, upstream of His1184.
• The PALB2 VCEP PVS1 materials establish loss of function as a relevant disease mechanism, and the variant-level PVS1 assessment identifies this frameshift as eligible for the generic PVS1 framework with suggested Very Strong strength.

Sources

Reasoning

The PALB2 VCEP Version 1.3 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; therefore no allele frequency exceeds the BA1 threshold. The available non-cancer subsets also report absence, but they do not alter the conclusion.

Rule

Grpmax Filtering AF >0.1% in gnomAD

Evidence considered

• PALB2 VCEP Version 1.3 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, with no allele count or frequency reported.
• The variant is also reported absent from the available gnomAD v2.1 and v3.1 non-cancer subsets.

Sources

Reasoning

The PALB2 VCEP Version 1.3 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 frequency reaches the BS1 threshold. The available non-cancer subsets likewise report absence.

Rule

Grpmax Filtering AF >0.01% in gnomAD

Evidence considered

• PALB2 VCEP Version 1.3 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, with no allele count or frequency reported.
• The variant is also reported absent from the available gnomAD v2.1 and v3.1 non-cancer subsets.

Sources

Reasoning

The PALB2 VCEP specifies PS4 Strong for case-control studies requiring p-value ≤.05 and either odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5. PMID:28779002 reported a group-level OR of 4.69 (95% CI 2.27–9.68; p=6.9×10−6) for PALB2 truncating variants in 13,087 cases and 5,488 controls, but explicitly did not report NM_024675.4:c.1049_1050insT or p.(Q350Hfs*11). Because the available enrichment estimate is for a heterogeneous truncating-variant group rather than this exact variant, the evidence is insufficient to assess PS4 for this variant; no exact-variant case-control counts or statistics are available.

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 is: "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 OR 4.69, 95% CI 2.27 to 9.68, p=6.9×10−6 for PALB2 truncating variants as a group, not for this exact variant.
• The paper's exact-variant search found no report of c.1049_1050insT or p.(Q350Hfs*11), so its group-level result cannot be assigned as exact-variant PS4 evidence.

Still missing

• Exact-variant case and control counts, odds ratio or relative risk, confidence interval, and p-value are unavailable.

Sources

Reasoning

The PALB2 VCEP permits PM3 for the autosomal-recessive Fanconi anemia context and requires proband-level evidence of this variant with a pathogenic or likely pathogenic PALB2 variant in trans, with points assigned according to phenotype, classification, and phase. The available evidence does not document this exact variant in an affected Fanconi anemia proband, a pathogenic/likely pathogenic variant in trans or in cis, parental/offspring phase testing, or a qualifying homozygous observation. Therefore no PM3 points can be assigned and no PM3 strength can be established.

Rule

PALB2 VCEP PM3: assign Fanconi anemia PM3 points per proband; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = at least 4 points, and PM3_VeryStrong = at least 8 points.

Evidence considered

• The PALB2 Version 1.3 specification states that PM3 is applicable for Fanconi anemia and assigns points per unrelated proband based on phenotype, the other variant's classification, and confirmed trans phase, homozygosity, or unknown phase.
• The available case records identify NM_024675.4:c.1049_1050insT as a PALB2 frameshift, but provide no affected Fanconi anemia proband, second pathogenic PALB2 allele, or phase result for this exact variant.
• The reviewed full-text extraction records for the five fetched papers do not report NM_024675.4:c.1049_1050insT or p.(Gln350HisfsTer11), and therefore provide no qualifying PM3 observation.

Still missing

• Affected Fanconi anemia proband(s) carrying NM_024675.4:c.1049_1050insT
• A pathogenic or likely pathogenic PALB2 allele identified in the same proband
• Confirmed trans phase, or homozygosity, by parental, offspring, or equivalent phase testing
• Fanconi anemia phenotype details sufficient to assign PALB2 VCEP PM3 points

Sources

Reasoning

PP1 is applicable under the PALB2 Version 1.3 VCEP specification, which mandates quantitative co-segregation analysis. The available case evidence contains no identified affected relatives, parental transmission results, meioses, pedigree, LOD score, or Bayes factor for NM_024675.4:c.1049_1050insT. Therefore, segregation evidence cannot be established or assigned a PP1 strength. The VCEP thresholds are PP1 Supporting at LOD ≥0.3 or LR ≥2:1, Moderate at LOD ≥0.60 or LR ≥4:1, and Strong at LOD ≥1.26 or LR ≥18:1.

Rule

PP1: Quantitative PALB2 co-segregation is required; 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 co-segregation analysis for PP1 and gives Supporting, Moderate, and Strong thresholds of LOD ≥0.3/LR ≥2:1, LOD ≥0.60/LR ≥4:1, and LOD ≥1.26/LR ≥18:1, respectively.
• No proband-specific pedigree, affected-relative testing, parental transmission, meiosis count, LOD score, or likelihood ratio was reported in the available case evidence.

Still missing

• Obtain a pedigree and phenotype-confirmed affected-relative data.
• Document variant testing and transmission status for each informative relative.
• Calculate quantitative co-segregation evidence as a LOD score or Bayes factor/likelihood ratio.

Sources

Reasoning

The PALB2 VCEP Version 1.3 requires BS2 point-based evidence from unaffected individuals or individuals with phenotypes inconsistent with PALB2-related disease, using its Fanconi anemia and cancer tables: supporting at 1 point, moderate at 2 points, and strong at 4 or more points. The population data available for this variant report only gnomAD absence and provide no homozygote observations, unaffected-carrier phenotypes, or BS2 points. BS2 therefore cannot be assessed.

Rule

BS2 supporting = 1 point; BS2 moderate = 2 points; BS2 strong = >=4 points, using the PALB2 Fanconi anemia and cancer BS2 tables

Evidence considered

• PALB2 VCEP Version 1.3 assigns BS2 by points from specified unaffected or phenotype-inconsistent individuals: supporting at 1 point, moderate at 2 points, and strong at 4 or more points.
• gnomAD v2.1 and v4.1 report the variant as absent and provide no homozygote, carrier-phenotype, or point-based BS2 observations.

Still missing

• No homozygote or unaffected-carrier observations with phenotype information are available.
• No PALB2 VCEP BS2 point calculation can be performed.

Sources

Reasoning

BS4 is applicable under the PALB2 Version 1.3 VCEP specification, which requires quantitative co-segregation analysis for lack of segregation. The available case evidence contains no affected relatives who tested negative for NM_024675.4:c.1049_1050insT, no phenotype-confirmed non-segregation observations, no meioses, LOD score, or Bayes factor. Therefore, BS4 cannot be assigned. The VCEP thresholds are BS4 Supporting at LOD ≤−0.32 or LR ≤0.48, Moderate at LOD ≤−0.64 or LR ≤0.23, and Strong at LOD ≤−1.28 or LR ≤0.053:1.

Rule

BS4: Quantitative PALB2 lack-of-segregation evidence is required; 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 requires quantitative co-segregation analysis for BS4 and gives Supporting, Moderate, and Strong thresholds of LOD ≤−0.32/LR ≤0.48, LOD ≤−0.64/LR ≤0.23, and LOD ≤−1.28/LR ≤0.053:1, respectively.
• The VCEP cautions that phenocopies and more than one pathogenic variant in a family can mimic lack of segregation; no family-level non-segregation data or quantitative result was reported in the available case evidence.

Still missing

• Obtain phenotype-confirmed affected relatives who were tested for the variant.
• Document reliable negative variant results and assess phenocopy or alternative-variant explanations.
• Calculate quantitative non-segregation evidence as a LOD score or Bayes factor/likelihood ratio.

Sources