Tumour sequencing reveals more — when is it worth following up?

UK Framework Proposed for Triage of Germline Variants Detected in Tumour Sequencing

McVeigh et al. have published a proposed framework to help clinicians decide which germline variants uncovered by tumour sequencing should trigger further testing.

Tumour sequencing often reveals variants that might be germline, but following up every finding is neither practical nor affordable within the National Health Service (NHS). To address this challenge, UK cancer genetics leaders reviewed current evidence, guidelines, and clinical practice to reach a national consensus on a streamlined approach.

The group recommends an “intermediate conservative” workflow: germline follow-up should be prioritised for the most actionable variants, including BRCA1, BRCA2, PALB2, mismatch repair genes, high-risk RET variants, and TP53 variants identified in patients younger than 30 years (excluding brain tumours). Variants should generally meet a variant allele fraction threshold of 30–40%, though known founder variants may be considered at lower levels. More restrictive follow-up is advised for lower-actionability genes or off-tumour findings.

This framework is designed to focus scarce NHS capacity on variants with the highest clinical utility, ensuring patients most likely to benefit are identified while avoiding unnecessary testing.

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Common Diagnoses May Mask Rare Genetic Disorders

A new study by Rahimov et al. highlights how patients diagnosed with common conditions such as multiple sclerosis (MS), inflammatory bowel disease (IBD), or atopic dermatitis may actually have rare monogenic disorders with overlapping symptoms. These hidden genetic causes can lead to misdiagnosis, inappropriate treatment, and misleading outcomes in clinical trials.

Researchers analysed exome and genome sequencing data from the UK Biobank, a research MS cohort, and five IBD clinical trials. They found that 1–3% of patients in these “common disease” cohorts harboured rare pathogenic variants consistent with monogenic disorders.

The most frequent single-gene culprits were NOTCH3 (associated with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL) in MS, TNFRSF13B (associated with common variable immunodeficiency) in IBD, and FLG (associated with ichthyosis vulgaris) in atopic dermatitis cohorts.

Recognising these hidden diagnoses can explain unusual disease severity or poor response to treatment, while also enabling targeted genetic counselling and cascade testing for family members. The authors argue that systematic genome sequencing and molecular phenotyping in both clinical care and trials could reduce misdiagnosis, improve therapy choices, and uncover new opportunities for treatment.

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Study Questions Reliability of HRR Variants as Markers for HRD in Ovarian Cancer

A UK study led by Morgan et al. has examined the relationship between homologous recombination repair (HRR) gene variants and homologous recombination deficiency (HRD) in high-grade ovarian carcinoma (HGOC).

While germline HRR testing and tumour HRD assays are now standard, HRD status — typically measured by genomic instability (GI) — may not consistently align with the presence or absence of HRR gene variants. Researchers analysed over 1,000 unselected HGOC cases from the North West Genomic Laboratory Hub, pairing germline and somatic HRR testing with tumour HRD assessment.

They found that more than 95% of BRCA1 pathogenic variant (PV) tumours exhibited high GI, compared with around 80% for BRCA2 and only around 50% for non-BRCA HRR PVs. This suggests that BRCA2 and other HRR gene variants are less reliable proxies for HRD status, and/or that current HRD assays do not detect all true HRD tumours.

The authors recommend considering retesting or rebiopsy in cases with borderline or failed HRD results, to better guide eligibility for poly (ADP-ribose) polymerase inhibitor (PARPi) therapy.

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