EXTERNAL QUALITY ASSESSMENT
6 5
4 3 2 1
0 0
3 5
50 50
100 100
Fig 5. Correct classifications obtained versus number of participants.
that participants came across were: n arr[GRCh37] 1q44 (247,815,979_ 248,609,997)x1 (variant 5) – only 17.7% of the participants assigned the expected classification Class 1 (benign) or Class 2 (likely benign).
n arr[GRCh37] 20q11.21q11.22 (29906675_33192526)x3 (variant 6) – among the 42 participants who encountered it, 50% correctly classified it as Class 4 (likely pathogenic), while the remaining 50% participants classified it as either Class 3 (variant of uncertain significance) or Class 5 (pathogenic).
n arr[GRCh38] 1q21.1 (145635445_ 146019823)x1 dn (variant 15) – 95% of the participants correctly assigned the expected classification Class 3 (variant of uncertain significance) or Class 4 (likely pathogenic) or Class 5 (pathogenic).
A total of 71 SNVs were available across the modules; Figure 4 displays data for 23 variants that were more frequently encountered by participants due to randomisation. The number of correct classifications is illustrated by dark blue bars, with alternative classification shown in light blue.
Overall, SNV classification was generally standardised, although variants 6, 8, and 19 showed greater variability (Figure 4). n BRCA1 NM_007294.4:c.1106_1108del p.(Asp369del) (variant 6) – among 34 participants, 50% classified it as Class 1 (benign) while the remainder classified it as Class 2 (likely benign), Class 3 (variant of uncertain significance), with 8.8% of participants assigning Class 4 (likely pathogenic) and 5.8% of participants assigning class 5 (pathogenic).
n BRCA1 NM_007294.4:c.661G>T p.(Ala221Ser) (variant 8)
– showed a notable variability: only 11% of the participants classified it correctly as Class 1 (benign), 44.4% participants classified it as Class 2 (likely benign) and the remainder 44.4% as Class 3 (variant of uncertain significance).
n NF1 NM_000267.3:c.846G>A p.(=) (variant 19)
– classification was most standardised with 70% participants classifying it correctly as Class 1 (benign). The 25% of participants classified it as Class 2 (likely benign) and only one participant assigned Class 4 (likely pathogenic).
BRCA1, BRCA2 and other HRR gene variant classification assessments From 2017 onwards, GenQA has collaborated with EMQN to conduct
Case Expected result for patient
Case 1 No genetic cause identified Case 2 No genetic cause identified
Case 3 Hemizygous SLC6A8
Case 4 No genetic cause identified
Case 5 Heterozygous de 0/12 novo TUBA1A
Case 6 Compound
heterozygous SBDS
Total 2/13 21% 16.1% 1.3% 3.4% Table 1. Summary of WGS/WES proportionate variant analysis.
WWW.PATHOLOGYINPRACTICE.COM DECEMBER 2025 47 12% 1.4% 1/89 1/90
(both variants exlcuded)
0.06% 0/22 1/26 12% 14% 2.0% 3.6% 2/88 n/a 1/26 14% 3.6% n/a
“Other” >” Expected” repsonses / total variants
3/12
150 150
Number of participants (n=359 completed all variants)
200 200
14 41 181 115
global biannual assessments focusing on BRCA1, BRCA2 and other HRR gene variants. The assessments are available during October and April. Participants are required to classify six variants per assessment within four weeks. Additionally, two interactive webinars per assessment are also provided that allow participants to understand accurate variant classification and clinical impact of variability, use of database, and best practice guidelines and their use. In the most recent assessment, also known as BRCA run 14, there were 359 participants from 58 countries. The overall performance showed a good standardisation of classifications with 181 (50%) participants correctly classifying all six variants while 115 (32%) correctly classified five variants (Figure 5). For this assessment, additionally to participation certificate and submission summary report, participants also receive a summary report that includes the results of the assessment, discussion points provided by the panel of expert advisors and answers to questions that have been submitted during the webinars and while the assessment is open for participation.
WGS/WES proportionate variant analysis assessment Since April 2025, an assessment for WGS/ WES proportionate variant analysis is also provided, aligned with the ACGS position statement.6
The pilot assessment was
available for three weeks and included six clinical WES/WGS case scenarios. The cases had between eight and 26 annotated variants for proportionate analysis. Proportionate variant analysis aids achieving fast and accurate analysis times by prioritising only the most
Responses Clinically relevant not as
deviations: “Expected” excluded ➔ 23% 6.9%
Clinically relevant deviations:
causative variants
“definitely report” ➔ excluded / total n/a
Number of correctly classified variants
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