Age-Based Genetic Testing Criteria May Overlook Inherited Cancer Risk

A large pan-cancer analysis published in Cancer Discovery found that restricting germline genetic testing to patients diagnosed before age 50 would miss most patients with pathogenic germline variants, including variants in genes with potential implications for cancer treatment and familial risk.^1,2

The study aimed to examine whether age at diagnosis could reliably identify patients most likely to carry inherited cancer-associated variants. The investigators found that although pathogenic variant prevalence was higher among patients with earlier-onset disease, clinically relevant variants were also identified among patients with average- and late-onset cancers.

Study Design: A Tumor-Specific Approach

Researchers evaluated germline sequencing results from 39,184 unselected patients with solid tumors spanning 32 tumor types at Memorial Sloan Kettering Cancer Center (MSK). Testing was performed using the MSK-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay, which assessed 94 germline pathogenic variants using DNA obtained from blood or saliva. Overall, 16.3% of patients harbored at least 1 germline pathogenic variant.

For the analysis, investigators categorized patients according to their age at diagnosis relative to the average age for their specific tumor type. Early-onset disease was defined as a diagnosis more than 1 standard deviation below the tumor-specific mean age, while late-onset disease was defined as a diagnosis more than 1 standard deviation above the mean. Patients diagnosed within 1 standard deviation of the tumor-specific mean were classified as having average-onset disease.

This approach allowed the investigators to account for differences in the typical age at diagnosis across the 32 tumor types included in the analysis rather than applying the same age threshold to every cancer. Germline sequencing was performed independent of clinical suspicion, allowing the investigators to assess the prevalence of pathogenic variants without restricting the analysis to patients who had already met conventional criteria for hereditary cancer evaluation.

Key Findings

Pathogenic germline variant prevalence was highest among patients with early-onset disease but remained substantial among those with later-onset cancers. Variants were identified in 18.4% of patients with early-onset tumors, 15.6% of those with average-onset tumors, and 12.3% of those with late-onset tumors (P <.001).

The difference was primarily attributable to high- and moderate-penetrance genes, with pathogenic variants in these genes identified in 12.4% of patients with early-onset disease, compared with 8.9% and 5.1% of patients with average- and late-onset disease, respectively (P <.001).

However, applying a conventional age-based testing threshold would have substantially reduced the number of patients identified. Restricting testing to patients diagnosed before age 50 would have missed 4601 pathogenic variant carriers, representing 72% of all carriers identified in the cohort.

Rethinking Age-Based Germline Testing

Age at diagnosis is commonly incorporated into criteria for hereditary cancer risk assessment, with genetic testing often considered for patients diagnosed with certain cancers at younger ages, including those diagnosed before age 50. These criteria are intended to identify patients with a higher likelihood of carrying an inherited cancer-predisposition variant while focusing testing on patients most likely to benefit from evaluation.

However, the study findings suggest that using age as a primary threshold may leave a substantial proportion of pathogenic variant carriers unidentified and may thus be insufficient for determining which patients with cancer should undergo germline testing. Although the prevalence of pathogenic variants was lower among patients with later-onset disease, the presence of inherited variants across the age spectrum indicates that clinically relevant germline findings are not limited to patients diagnosed at younger ages.

The tumor-specific approach used in the study also highlights a limitation of applying a single chronological cutoff across cancer types. Because the expected age at diagnosis varies by tumor type, a uniform threshold may not adequately capture patients whose age at diagnosis is unusual for their specific malignancy.

Overall, the findings support consideration of broader germline testing across patients with cancer, regardless of age at diagnosis. Broader germline testing could increase identification of patients with inherited cancer predisposition who might otherwise be excluded based on age.

“These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases,” authors Stadler et al wrote.

REFERENCES

1. Stadler ZK, Maio A, Khurram A, et al. Universal Germline Genetic Testing after a Diagnosis of Cancer. Cancer Discovery. Published online October 8, 2026:OF1-OF9. doi:10.1158/2159-8290.cd-26-0971

2. Current Age-based Genetic Testing in Patients With Cancer May Miss Majority of Inherited Gene Variants. News release. American Association for Cancer Research. October 8, 2026. Accessed October 8, 2026. https://tinyurl.com/3v8u3spr