How do i determine the allelic frequency of my HRR SNPs

How to Determine the Allelic Frequency of Your HRR SNPs

This is a practical and important question. Let me walk you through what allelic frequency means, where to find it, and what to do if you don't have it.

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1) WHAT IS ALLELIC FREQUENCY? (The Basics)

Allelic Frequency = the percentage of your cancer cells that carry a specific mutation.

Think of it this way:

• If you have 100 cancer cells, and 30 of them have the HRR SNP mutation, your allelic frequency is 30%
• If only 5 of them have it, your allelic frequency is 5%

Why This Matters for Treatment: According to the Cancer Patient Lab Molecular Tumor Board discussion with Dr. [removed] Subudhi, the threshold for "actionability" is typically:

• 25% or higher = actionable (likely to respond to PARPi)
• Below 25% = not considered actionable by standard criteria

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2) WHERE TO FIND YOUR ALLELIC FREQUENCY

Option A: Your Genetic Test Report (Most Common)

If you've had tumor genetic testing (like Foundation One, Tempus, Guardant, or similar), your report should include allelic frequency information.

Look for these sections in your report:

✅ "Variant Allele Frequency" (VAF) - This is the standard term

• Usually shown as a percentage (e.g., "VAF: 28%")
• May also be shown as a decimal (e.g., "0.28")

✅ "Allelic Fraction" - Another common term for the same thing

✅ "Tumor Mutational Burden" or "TMB" section - Sometimes includes VAF data

✅ "Mutation Details" or "Detailed Findings" table** - Lists each mutation with its frequency

Example from a typical report:

Gene: ATM
Mutation: c.1234A>G
Variant Allele Frequency: 22%
Classification: Likely pathogenic

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Option B: Contact Your Testing Company Directly

If your report doesn't clearly show allelic frequency:

Step 1: Identify which company did your test

• Foundation One (FoundationOne CDx or FoundationOne Liquid)
• Tempus (xT or xLiquid)
• Guardant (GuardantOMNI or Guardant360)
• Invitae
• Myriad
• Other labs

Step 2: Call their patient support line

• Ask: "I have a genetic test result. Can you provide the variant allele frequency (VAF) or allelic fraction for my mutations?"
• Have your test report number ready
• They can often email you a more detailed technical report

Step 3: Ask specifically about your HRR SNP

• "I'm interested in the allelic frequency for my [specific gene name] mutation. Is it above or below 25%?"

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Option C: Ask Your Oncologist

This is often the easiest approach:

Your oncologist should have:

1. Your full genetic test report (with VAF data)
2. The ability to interpret what the allelic frequency means for YOUR case
3. Context about whether it's actionable for PARPi treatment

What to ask:

• "What is the allelic frequency of my HRR SNP?"
• "Is it above the 25% threshold for being considered actionable?"
• "Has this frequency changed on any repeat testing?"

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3) UNDERSTANDING DIFFERENT TYPES OF GENETIC TESTS

This matters because allelic frequency interpretation differs:

Tissue Biopsy (Tumor Tissue Sample)

• Most reliable for allelic frequency
• Shows what percentage of cancer cells in that specific tumor location have the mutation
• Example: Pathology report from a biopsy or surgery

How to find it:

• Look in your pathology report under "Molecular Testing" or "Genetic Testing"
• May be labeled as "Next-Generation Sequencing (NGS) Results"

Liquid Biopsy (Blood Test)

• More variable - shows mutations circulating in bloodstream
• May underestimate allelic frequency (some mutations don't shed into blood equally)
• Examples: Foundation One Liquid, Guardant360, Tempus xLiquid

Important caveat from Cancer Patient Lab: According to "The BostonGene Tumor Portrait Report and How to Access It" webinar, liquid biopsies have important limitations:

• Different sensitivity and sequencing depth between companies
• May show false negatives (mutation present in tumor but not detected in blood)
• May show false positives in rare cases
• Tissue biopsy is generally more accurate for allelic frequency

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4) WHAT IF YOUR REPORT DOESN'T SHOW ALLELIC FREQUENCY?

This happens sometimes, especially with older reports.

Step 1: Request a Re-analysis

Many testing companies will re-analyze your sample at no cost if you ask:

• "Can you provide a detailed technical report that includes variant allele frequency for all mutations?"

Step 2: Consider Repeat Testing

According to the Elliot Davis Molecular Tumor Board discussion, repeat testing can be valuable because:

• Allelic fractions change over time as cancer evolves
• A mutation that was low-frequency might become high-frequency (suggesting the cancer is selecting for it)
• This evolution is clinically important for treatment decisions

When to consider repeat testing:

• If your original test is more than 1 year old
• If you've had multiple lines of treatment since the original test
• If your PSA is rising despite treatment (suggests cancer evolution)
• If your oncologist recommends it to guide next treatment decisions

Step 3: Ask About Liquid Biopsy Monitoring

According to Dr. [removed] Subudhi's discussion, serial liquid biopsies can track:

• Whether your HRR SNP frequency is increasing
• Whether new mutations are emerging
• How your cancer is evolving under treatment pressure

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5) INTERPRETING YOUR ALLELIC FREQUENCY RESULTS

Once you have the number, here's how to think about it:

| Allelic Frequency | Clinical Interpretation | PARPi Consideration | |---|---|---| | ≥25% | High frequency, likely clonal (present in most cancer cells) | Actionable - PARPi may be appropriate | | 10-24% | Moderate frequency, present in subset of cells | Potentially actionable - depends on context | | <10% | Low frequency, present in minority of cells | Not typically actionable - but monitor for changes |

Important context from Dr. [removed]:

• A rising allelic fraction over time (even if starting low) suggests the cancer is selecting for that mutation
• This makes it more actionable even if currently below 25%
• Example: If your HRR SNP was 8% six months ago and is now 18%, that upward trend is clinically significant

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6) QUESTIONS TO ASK YOUR ONCOLOGIST

Once you have your allelic frequency number:

1. "What is the allelic frequency of my HRR SNP, and is it above the 25% actionability threshold?"

2. "Is this mutation present in all my cancer cells (clonal) or just some of them (subclonal)?"

3. "Has this allelic frequency changed on any previous testing? Is it trending up or down?"

4. "Given my specific allelic frequency, do you think a PARPi combination would be appropriate for me?"

5. "Would you recommend repeat genetic testing to monitor whether this mutation's frequency is changing?"

6. "Should I have a tissue biopsy or liquid biopsy to get the most accurate allelic frequency measurement?"

7. "Are there clinical trials specifically for patients with HRR mutations at my allelic frequency level?"

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7) PRACTICAL NEXT STEPS

Here's what to do RIGHT NOW:

Step 1: Gather your reports

• Find your genetic test report (Foundation One, Tempus, Guardant, etc.)
• Look for "Variant Allele Frequency" or "All