NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant in PALB2 exon 4. Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for PALB2 v1.2.0, missense pathogenic variation is not yet confirmed as a mechanism of disease.1 The variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.01511% (206/1,614,002 alleles), exceeding the PALB2 VCEP BS1 threshold of >0.01%, meeting BS1 at Strong strength.2 BP1 (Supporting benign) is met per VCEP rule that applies to all PALB2 missense variants, as true missense pathogenic variants in PALB2 are thought to be exceedingly rare.3 The gnomAD v4.1 frequency (0.01511%) does not reach the BA1 threshold (>0.1%) or the PM2 threshold (<=0.000333%). In silico predictions (SpliceAI max delta=0.02, REVEL=0.034, BayesDel=-0.732) are not used under this VCEP for missense variants per PP3/BP4 rules.4 No case-control studies, co-segregation data, or Fanconi Anemia biallelic observations were available to assess PS4, PP1, BS2, or BS4.5 Applying the PALB2 VCEP/ACMG combination rules: one Benign Strong criterion (BS1) plus one Benign Supporting criterion (BP1) is consistent with a Likely Benign classification per Rule 18.6
PALB2
Final classification
Likely Benign
PALB2 c.928A>G · p.Ser310Gly
PALB2
NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant in PALB2 exon 4. Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for PALB2 v1.2.0, missense pathogenic variation is not yet confirmed as a mechanism of disease.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP1 supporting benign; maps to Likely Benign.
Classification rationale
BS1BP1
Likely Benign
PALB2 c.928A>G
BS1 + BP1
→
Likely Benign
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
206 / 1,614,002
0.013%
Highest · European (non-Finnish)
0.017%
Homozygotes
0
grpmax FAF
0.015%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 201 / 1,179,992 | 0.017% | 0 |
| Admixed American | 0 / 59,996 | — | — |
| European (Finnish) | 0 / 64,036 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,894 | — | — |
| Middle Eastern | 0 / 6,084 | — | — |
| South Asian | 0 / 91,078 | — | — |
| Ashkenazi Jewish | 0 / 29,602 | — | — |
| African/African American | 0 / 74,928 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 0.000127633; MAF= 0.01276%, 206/1614002 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00017034; MAF= 0.01703%, 201/1179992 alleles, homozygotes = 0); grpmax FAF= 0.00015106.
Overall AF
12 / 251,176
0.0048%
Highest · European (non-Finnish)
0.011%
Homozygotes
0
grpmax FAF
0.006%
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 12 / 113,616 | 0.011% | 0 |
| African/African American | 0 / 16,190 | — | — |
| Admixed American | 0 / 34,564 | — | — |
| Ashkenazi Jewish | 0 / 10,078 | — | — |
| East Asian | 0 / 18,394 | — | — |
| European (Finnish) | 0 / 21,620 | — | — |
| Remaining individuals | 0 / 6,116 | — | — |
| South Asian | 0 / 30,598 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 4.77753e-05; MAF= 0.00478%, 12/251176 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000105619; MAF= 0.01056%, 12/113616 alleles, homozygotes = 0); grpmax FAF= 6.019e-05.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 128149)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.034. BayesDel score = -0.732133.
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 previously been reported in somatic cancers (COSMIC; COSV55167149, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 22 PMIDs triaged · 8 high-priority
22papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
26635394 ↗
functional
RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins.
Transcription factors bind to the genome by forming specific contacts with the primary DNA sequence; however, RNA-binding proteins (RBPs) have greater scope to achieve binding specificity through the RNA secondary structure. It has been revealed that single nucleotide variants (SNVs) that alter RNA structure, also known as RiboSNitches, exhibit 3-fold greater local structure changes than replicate
BS3PP5PS3PS4
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17200668 ↗
case observation
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.
PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) =
PP5PS4
17508274 ↗
case observation
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
PP5PS4
18163131 ↗
case observation
The emerging landscape of breast cancer susceptibility.
The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alle
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links