Table 3. Clinical feasibility of PARP inhibitors in patients harboring pathogenic BRCA1/2 mutations and in two sisters carrying the BRCA2 VUS p.S1946P.

ID	Variant classification	Gene	Amino acid change#	Variant frequency (%)	Germline (G)/ somatic (S)	LOH/ biallelic inactivation	Eligibility for PARPi (USFDA label)	Eligibility for PARPi (EMA label)
1	pathogenic	BRCA2	p.S1722fs	78	G	Yes	Yes	Yes
2	pathogenic	BRCA2	p.S1722fs	74	G	Yes	Yes	Yes
3	pathogenic	BRCA1	p.E730*	77	G	Yes	Yes	Yes
4ψ	pathogenic	BRCA1	p.T796I	53	G	Unknown§	Yes	Yes
5	pathogenic	BRCA1	p.Œ_splice	78	G	Yes	Yes	Yes
6	pathogenic	BRCA1	p.S1286fs	62	G	Yes	Yes	Yes
7	pathogenic	BRCA2	p.S780*	80	G	Yes	Yes	Yes
8	pathogenic	BRCA2	p.E260fs	75	G	Yes	Yes	Yes
9	pathogenic	BRCA1	p.S242fs	79	S	Yes	No	Yes
10	pathogenic	BRCA1	p.F989fs	59	S	Yes	No	Yes
11	pathogenic	BRCA1	p.G1738fs	68	S	Yes	No	Yes
12	pathogenic	BRCA2	p.D1451fs	43	S	Yes	No	Yes
13	VUS	BRCA2	p.S1946P	75	G	Yes	Yes¶	Yes¶
14	VUS	BRCA2	p.S1946P	48	G	No	Yes¶	Yes¶
Patients eligible for PARPi (Yes/Unknown/No)							10/0/4	14/0/0

ψPatient 4 harbored an additional somatic pathogenic BRCA2 variant characterized by a low frequency (6%). #HGVSp - the Human Genome Variation Society (HGVS) protein sequence name. The Annotation is based on the BRCA1 transcript ENSG00000012048 (NM_007294) and the BRCA2 transcript ENSG00000139618 (NM_000059). §The SNP analysis did not allow a conclusion about the presence of an LOH. ¶Based on the assumption that the VUS p.S1946P can be classified as pathogenic.

Abbreviations: EMA, European Medicines Agency; LOH, loss of heterozygosity;PARPi, poly (ADP-ribose) polymerase inhibitors; USFDA, United States Food and Drug Administration; VUS, variant of uncertain significance.