The PALB2 c.1960A>G (p.Ile654Val) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission, and no expert panel classification was identified.1 This variant is present in gnomAD v4 at 0.00043% overall (7/1,614,140 alleles) with a highest observed population frequency of 0.00769% in South Asians, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.2 Under the PALB2 expert specification, BP1 is met because this is a missense variant in a gene for which established pathogenic variation is predominantly truncating.3 SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01); REVEL is 0.043 and BayesDel is -0.826097, although the PALB2 expert specification does not use PP3 or BP4 for missense prediction alone.4
Final classification
VUS
BP1
PALB2
c.1960A>G
p.Ile654Val
This variant
The PALB2 c.1960A>G (p.Ile654Val) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission, and no expert panel classification was identified.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.
Classification rationale
BP1
VUS
PALB2 c.1960A>G
BP1
→
VUS
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.
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BP1
supporting
Benign
This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because established pathogenic PALB2 variation is predominantly truncating.
NM_024675.4:c.1960A>G predicts NP_078951.2:p.(Ile654Val) / p.(I654V).PALB2 CSPEC states BP1 applies to all missense variants.
Assessed · not applied
· 4 not met · 5 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a predicted loss-of-function variant, and the generic PVS1 scaffold specifically notes that it does not fall within the usual null-variant categories, so PVS1 is not met.
PS4
No qualifying case-control study showing significant enrichment of this exact variant in affected individuals was identified, so PS4 cannot be applied.
PM2
This variant is present in gnomAD v4 at 0.00043% (7/1,614,140 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 cannot be assessed.
PP1
No segregation data were identified for this variant, so PP1 cannot be assessed.
Benign
BA1
The highest observed gnomAD v4 population frequency is 0.00769%, which is well below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.
BS1
The highest observed gnomAD v4 population frequency is 0.00769% in South Asians, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.
BS2
No qualifying observations in healthy adult individuals or other evidence meeting the PALB2 BS2 point-based framework were identified.
BS4
No quantitative non-segregation data were identified, so the PALB2 BS4 thresholds cannot be evaluated for this variant.
N/A · 18
PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.33667e-06; MAF= 0.00043%, 7/1614140 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 7.68521e-05; MAF= 0.00769%, 7/91084 alleles, homozygotes = 0); grpmax FAF= 3.587e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.96324e-06; MAF= 0.00080%, 2/251154 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53296e-05; MAF= 0.00653%, 2/30614 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,614,140
0 hom · FAF 0.0036%
0 hom · FAF 0.0036%
South Asian 7 / 91,084 |
0.0077% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0008%
· 2 / 251,154
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
South Asian 2 / 30,614 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 234115)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.043. BayesDel score = -0.826097.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
27648926 ↗
Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.
CLINVAR
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR