Table 3.

Evaluation of the supporting data provided in BRCA1/2 databases for the pathogenic classification of 18 challenging variants as measured by evidence-based guidelines for variant interpretation of “likely pathogenic”(Lyon et al. 2013; Richards et al. 2014)

	BIC	ClinVar	LOVD	UMD
BRCA1 c.2351C>T p.Ser784Leu	VUS	Benign Data: nonea Insufficient	Pathogenic Data: literature Insufficient	VUS
BRCA1 c.3082C>T p.Arg1028Cys	VUS	Benign Data: nonea Insufficient	Pathogenic Data: literature Insufficient	VUS
BRCA1 c.4484G>T p.Arg1495Met	Pathogenic Data: none Insufficient	Pathogenic Data: nonea Insufficientb	Pathogenic Data: literaturec Sufficient	Pathogenic Data: literatured Sufficient
BRCA1 c.4868C>G p.Ala1623Gly	VUS	Pathogenic Data: nonea Insufficiente	Pathogenic Data: literature Sufficient	Pathogenic Data: literatured Sufficient
BRCA1 c.5072C>T p.Thr1691Ile	VUS	VUS	Pathogenic Data: literature Insufficient	VUS
BRCA1 c.4986+6T>C (IVS16+6T>C)	Pathogenic Data: none Insufficient	Pathogenic Data: nonea Insufficiente	VUS	Pathogenic Data: literatured Sufficient
BRCA1 c.5074G>C p.Asp1692His	Pathogenic Data: none Insufficient	Pathogenic Data: nonea Insufficiente	VUS	Pathogenic Data: literatured Insufficient
BRCA1 c.5408G>C p.Gly1803Ala	VUS	VUS	Benign Data: literature Insufficient	Pathogenicf Data: literatured Insufficientf
BRCA2 c.6290C>T p.Thr2097Met	VUS	Pathogenic Data: nonea,g Insufficiente	VUS	VUS
BRCA2 c.6322C>T p.Arg2108Cys	VUS	VUS	Pathogenic Data: literature Insufficient	VUS
BRCA2 c.7007G>A p.Arg2336His	Pathogenic Data: none Insufficient	Pathogenic Data: nonea Insufficientb	Pathogenic Data: literature Sufficient	Pathogenic Data: literatured Sufficient
BRCA2 c.7565C>T p.Ser2522Phe	VUS	VUS	Pathogenic Data: Literature Insufficient	VUS
BRCA2 c.7868A>G p.His2623Arg	VUS	Pathogenic Data: nonea Insufficientb	Pathogenic Data: literature Insufficient	VUS
BRCA2 c.7878G>C p.Trp2626Cys	VUS	VUS	Pathogenic Data: literature Sufficient	VUS
BRCA2 c.8168A>G p.Asp2723Gly	VUS	VUS	Pathogenic Data: literature Sufficient	Pathogenic Data: literatured Sufficient
BRCA2 c.9104A>C p.Tyr3035Ser	VUS	VUS	Pathogenic Data: literature Insufficient	VUS
BRCA2 c.9235G>A p.Val3079Ile	VUS	Pathogenic Data: noneag Insufficiente	Benign Data: literature Insufficient	VUS
BRCA2 c.9371A>T p.Asn3124Ile	VUS	Pathogenic Data: nonea Insufficientb	Pathogenic Data: literature Sufficient	VUS
Share of pathogenic classifications with sufficient evidence	0/4 0 %	0/11 0 %	6/15 40 %	5/7 71 %

“Pathogenic” or “VUS” refers to the classification made in the associated database for the variant according to the groupings defined in Table 1. For variants listed as pathogenic, “data” describes the type of data provided in the associated database to support the classification. “Sufficient” or “insufficient” represents whether or not the supporting data provided or referenced by the database is verifiable and meets the minimal requirements for a “likely pathogenic” classification according to ACMG/AMP/CAP evidence-based criteria (Lyon et al. 2013; Richards et al. 2014)

^aClassification was submitted to ClinVar from the Sharing Clinical Reports Project (http://sharingclinicalreports.org/), but no supporting evidence provided in the ClinVar display

^bAt the time of the initial ClinVar evaluation (November 6, 2013), ClinVar database did not provide supporting data for the clinical classification. However, at the time of manuscript preparation (March 11, 2014), the database listed an additional entry for the variant, which lacked a clinical classification, but did provide literature references which did not provide sufficient verifiable evidence required to meet minimal ACMG standards for at least a likely pathogenic classification

^cLOVD listed both pathogenic and uncertain classifications (see Table 1) for this variant where the literature associated with the uncertain classification did provide sufficient verifiable evidence to meet minimal ACMG standards for a likely pathogenic classification, but the literature associated with the listed pathogenic classification did not meet these standards

^dUMD frequently provides the age of disease onset in anonymized patients who have been reported by UMD’s contributors as carrying the variant. However, for the variants reported here, literature references were the primary data source for variant classification

^eSame as table footnote “b” for ClinVar, except that the entry added after our initial evaluation listed literature references which did meet minimal ACMG standards for a likely pathogenic classification, though the added entry did not provide a clinical classification

^fThe database lists a pathogenic classification, but the supporting data trends for a contrary (benign) classification

^gClinVar displays the most recent classification submitted from the Sharing Clinical Reports Project. At the time of the initial ClinVar evaluation (November 6, 2013), ClinVar database displayed a “pathogenic” classification” from the Sharing Clinical Reports Project. At the time of manuscript preparation (March 11, 2014), ClinVar displayed a “benign” or “likely benign” classification from the Sharing Clinical Reports Project