Reasons and Resolutions for Inconsistent Variant Interpretation

Table 1

Summary of interlaboratory discrepancy rates reported in the literature.

No.	Article	Number of variants	Source of variants	Enrichment time	Disease types	Inconsistent rate
						Five-tier	Three-tier	MSDs	VUS vs. LB/B
1	Amendola et al., 2016 [11]	99	9 CSER labs	Before Dec 2015	Unlimited	66%→29%	41%→14%	22%→5%	19%→9%
2	Garber et al., 2016 [15]	293	EGL and 4 labs on ClinVar	Before Jun 2015	Neuromuscular disorders, skeletal dysplasia, and short stature	56.7% (163/293)	33% (98/293)	N.M.	N.M.
3	Furqan et al., 2017 [32]	112	SHaRe	Before Mar 2015	Hypertrophic cardiomyopathy	N.M.	20.5%→10.7%	17%→9.8%	N.M.
		695	ClinVar			N.M.	45.20%	N.M.	N.M.
4	Harrison et al., 2017 [16]	6169	4 labs on ClinVar	Before Jan 2016	Unlimited	N.M.	11.7%→8.3%	5%→2%	N.M.
5	Yang et al., 2017 [27]	27224	ClinVar	Before Oct 2016	Unlimited	N.M.	MC: 89.3%; CC: 81%	MC: 96.7%; CC: 94.1%	N.M.
6	Harrison et al., 2018 [48]	49242	686 submitters on ClinVar	Before Apr 2017	Unlimited	N.M.	22.20%	4.30%	N.M.
		24445	41 clinical labs		Unlimited	N.M.	15.40%	2.70%	N.M.
7	Amendola et al., 2020 [31]	158	8 CSER labs	Before Aug 2020	59 genes reported by accidental discovery	16%	29.8%→10.8%	11%→4.4%	N.M.

Five-tier inconsistent rate: P vs. LP vs. VUS vs. LB vs. B. Three-tier inconsistent rate: P/LP vs. VUS vs. LB/B. MSDs, medically significant difference: P/LP vs. VUS/LB/B. The number marked by “” is the consistent rate. CSER: Clinical Sequencing Exploratory Research consortium, EGL: Emory Genetics Laboratories, SHaRe: Sarcomeric Human Cardiomyopathy Registry, N.M.: not mention, CC: complete consensus, MC: major consensus. If a variant is graded by 3 or more laboratories, the degree of agreement can be divided into CC and MC [27]. CC means that all laboratories have the same classification results, while MC indicates that the majority have the same classification results. The definition of “majority” is that the agreed laboratories account for two-thirds or more of all laboratories.