Prevalence of BRCA1 and BRCA2 germline variants in an unselected pancreatic cancer patient cohort in Pakistan

Table 3 In silico analyses and classification of BRCA1/2 variants

	VarCards in silico predictions				ACMG-AMP criteria^d	Classification
Coding variants	D/A algorithms^a	Damaging score^b	Extreme^c
BRCA1
p.Thr293Ser	15/23	0.65	Yes		PM1, PP3, BP1	VUS
p.Val1740Met	18/23	0.78	Yes		PM1, PM2, PP3, BP1, BS3	Likely benign
BRCA2
p.Ile2296Leu	10/23	0.43	No		PM1, PP3, BP1	VUS
p.Glu2650Gln	20/23	0.87	Yes		PM1, PM2, PP3, BP1	VUS
p.Val928Asp	6/23	0.26	No		PM1, PM2, BP1, BP4	Likely benign
p.Ser1424Phe	1/23	0.04	No		PM1, PM2, BP1, BP4	Likely benign
p.Asp2438Tyr	6/23	0.26	No		PM1, PM2, PB1, BP4	Likely benign
p.Cys2636Arg	8/23	0.35	No		PM1, PM2, PB1, BP4	Likely benign
Non-coding variants	Alamut splice-site predictions^e				ACMG-AMP criteria^d	Classification
Non-coding variants	SSF-like	MaxEnt-Scan	NNSPLICE	Gene-Splicer	ACMG-AMP criteria^d	Classification
BRCA1
c.547 + 36A > G	NE	NE	NE	NE	PM2, BP4	Benign
c.4358-61C > G	NE	NE	NE	NE	PM2, BP4	Benign
c.4675 + 80C > T	NE	NE	NE	NE	PM2, BP4	Benign
c.5152 + 41 T > C	NE	NE	NE	NE	PM2, PP5, BP4	Benign
BRCA2
c.1910-21A > T	NE	NE	NE	NE	PM2, BP4	Benign

ACMG-AMP American College of Medical Genetics and Genomics and Association of Molecular Pathology, NE no effect, VUS variant of uncertain significance
^aNumber of algorithms predicted to be deleterious out of total in silico algorithms
^bProportion of algorithms predicted to be deleterious. Damaging score of loss-of-function variants is deemed to be 1
^cThe loss-of-function and damaging (score > 0.5) non-synonymous variants with allele frequency < 0.01% are regard as extreme variants
^dPredicted by PathoMan and/or InterVar tools with manual adjustment
^e > 20% change in score (i.e., a wild-type splice-site score decreases, and/or a cryptic splice-site score increases) is considered as significant

ISSN: 1897-4287