Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Dominguez-Valentin, Mev; Evans, D. Gareth R.; Nakken, Sigve; Tubeuf, Hélène; Vodak, Daniel; Ekstrøm, Per Olaf; Nissen, Anke M.; Morak, Monika; Holinski-Feder, Elke; Martins, Alexandra; Møller, Pål; Hovig, Eivind

doi:10.1186/s13053-018-0086-0

Hereditary Cancer in Clinical Practice

Table 2 RNA splicing- dedicated in silico analyses for the VUS identified in our study

From: Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Patient ID	Genomic position (GRCh37)	Gene	Exon	Nucleotide change (cNomen)	Predicted protein change (pNomen)	dbSNPrsID	Non-Finnish European population frequency*	Reference splice site-dedicated analyses								Cryptic splice site-dedicated analyses			ESR-dedicated analyses
								Nearest reference		MES scores			SSFL scores			Potential local splice effect	Local MES scores		∆tESRseq	∆Hzei	ΔΨ
								Distance	Type	WT	Var	VAR vs WT	WT	Var	VAR vs WT		WT	Var
								(nt)	(3′ or 5’ss)	WT	Var	∆ (%)	WT	Var	∆ (%)		WT	Var
688	chr_16_68835593_G_A	CDH1	3	c.184G > A	p.Gly62Ser	587,781,898	5.99e-05	21	3’	8.17477	8.17477	0	86.5179	86.5179	0				− 1.44947	10.35	−1.24
	chr2_47703664_G_A	MSH2	13	c.2164G > A	p.Val722Ile	587,781,996	8.99e-05	−47	5’	10.8583	10.8583	0	100	100	0				0.59756	10.51	−0.01
	chr_8_90983475_C_A	NBN	6	c.628G > T	p.Val210Phe	61,754,796	0.0008158	44	3’	6.19815	6.19815	0	86.8244	86.8244	0				− 0.782222	−46.21	− 0.15
1873	chr_5_56155672_A_G	MAP3K1	3	c.764A > G	p.Asn255Ser	56,069,227	0.0269	−71	5’	7.52484	7.52484	0	78.4708	78.4708	0	New Acceptor Site?	–	8.8	−1.18661	6.7	−0.04
5378	chr 12_133244944_G_A	POLE	19	c.2171C > T	p.Ala724Val	61,734,163	0.00030	−3	5’	9.89081	8.73118	−11.7	86.6769	82.5488	−4.8	New Donor Site?	–	6.3	−2.14822	−32.05	−0.16
6031	chr17_41245621_T_C	BRCA1	10	c.1927A > G	p.Ser643Gly	80,357,105	NA	1257	3’	8.86265	8.86265	0	87.3058	87.3058	0				1.44078	58.08	0.02
		AXIN2	10	c.2272G > A	p.Ala758Thr	145,007,501	0.0039861	35	3’	6.34671	6.34671	0	86.1925	86.1925	0				−0.942617	0.12	−0.09
	chr5_112102960_C_T	APC	4	c.295C > T	p.Arg99Trp	139,196,838	0.0006444	75	3’	7.49577	7.49577	0	84.8039	84.8039	0				−2.2189	−14.34	− 0.08
12,470		AXIN2	10	c.2272G > A	p.Ala758Thr	145,007,501	0.0039861	35	3’	6.34671	6.34671	0	86.1925	86.1925	0				−0.942617	0.12	− 0.09
12,470	chr5_112128218_G_A	APC	7	c.721G > A	p.Glu241Lys	777,603,154	0.0001818	−9	5’	7.15277	7.15277		87.0697	87.0697	0				−1.51981	−49.76	−0.42
12,852	chr_14_69061228_G_A	RAD51B RAD51B	11	c.1063G > A	p.Ala355Thr	61,758,785	0.0071658	27	3’	11.8	11.8	0	80.2	80.2	0	–	–	–	−1.24035	−50.64	–
88,295	chr10_89690828_G_A	PTEN PTEN	4	c.235G > A	p.Ala79Thr	202,004,587	0.0001678	−19	5’	9.6515	9.6515	0	86.8647	86.8647	0				−1.39321	10.77	0.6
900,178	chr11_94197365_C_T	MRE11A MRE11A	11	c.1139G > A	p.Arg380His	587,781,646	4.5e-05	41	3’	8.9941	8.9941	0	95.7456	95.7456	0				−1.57887	−48.78	−0.03
960,579	chr_5_56177843_C_G	MAP3K1	14	c.2816C > G	p.Ser939Cys	45,556,841	0.0221	447	3’	12.0063	12.0063	0	100	100	0	–	–	–	−0.486881	−16.1	0
1,000,459	chr13_28537449_ACTT_A	CDX2	3	c.742_744del	p.Lys248delAAG	553,066,746	0.0001682	55	3’	11.7045	11.7045	0	87.4307	87.4307	0				−2.46964	−100.08	–
1,100,948	chr_17_7133187_A_G	DVL2 DVL2	5	c.596 T > C	p.Met199Thr	372,715,697	6.01e-05	−61	5’	6.34467	6.34467	0	80.4452	80.4452	0				0.0509416	−1.77	0.54
1,100,948	chr2_47641430_C_T	MSH2	5	c.815C > T	p.Ala272Val	34,136,999	0.0003755	23	3’	10.3527	10.3527	0	84.3224	84.3224	0				−2.17832	−46.5	−0.03
10,002,068	chr_17_63526198_C_T	AXIN2	11	c.2428G > A	p.Asp810Asn	140,344,858	1.5e-05	23	3’	11.6727	11.6727	0	87.3948	87.3948	0				−1.22987	−14.33	–
10,005,829	chr_14_69061228_G_A	RAD51B	11	c.1063G > A	p.Ala355Thr	61,758,785	0.0071658	27	3’	11.8	11.8	0	80.2	80.2	0	–	–	–	−1.24035	−50.64	–
	chr8_90993640_C_T	NBN	3	c.283G > A	p.Asp95Asn	61,753,720	0.0030459	−38	5’	10.7663	10.7663	0	94.6711	94.6711	0				0.318238	24.6	0.03
	chr_11_108155132_G_A	ATM	26	c.3925G > A	p.Ala1309Thr	149,711,770	0.0009147			9.98517	9.98517	0	84.8076	84.8076	0				0.676556	32.96	0.04
12,001,161	chr_14_68353893_A_G	RAD51B	7	c.728A > G	p.Lys243Arg	34,594,234	0.010682	−29	5’	9.09184	9.09184	0	78.9497	78.9497	0	Cryptic 5’ss activation?	0.9	7.9	−1.48785	−40.54	−0.19
12,015,576	chr19_15291551_C_G	NOTCH3	19	c.3083G > C	p.Trp1028Ser	rs146829488	na	−60	5’	11.1124	11.1124	0	82.5954	82.5954	0				0.300115	−6.4	0.1
11,717	chr1_45797881_C_T	MUTYH	10	c.881G > A	p.Cys294Tyr	rs879254257	na	−44	5’	6.31089	6.31089	0	72.818	72.818	0				1.09496	−7.06	0.04
17,161	chr_11_108139187_T_A	ATM	18	c.2689 T > A	p.Phe897Ile	147,122,522	4.5e-05	51	3’	9.8979	9.8979	0	93.4253	93.4253	0				0.554269	87.95	0.01
22	chr_12_133241897_A_G	POLE	21	c.2459 T > C	p.Met820Thr	767,460,640	0	−10	5’	6.58677	6.58677	0	77.9039	77.9039	0				1.28743	−2.13	0.06
	chr_14_68352672_A_G	RAD51B	6	c.539A > G	p.Tyr180Cys	28,910,275	0.0045906	−34	5’	9.54919	9.54919	0	83.7411	83.7411	0				0.881539	7.23	−0.19
	chr_5_56155672_A_G	MAP3K1	3	c.764A > G	p.Asn255Ser	56,069,227	0.0269	−71	5’	7.52484	7.52484	0	78.4708	78.4708	0	New Acceptor Site?	–	8.8	−1.18661	6.7	−0.04
6207	chr_17_63530163_C_T	AXIN2	10	c.2272G > A	p.Ala758Thr	145,007,501	0.0039861	35	3’	6.34671	6.34671	0	86.1925	86.1925	0				−0.942617	0.12	−0.09
6475	chr_17_33433488_G_A	RAD51D	6	c.493C > T	p.Arg165Trp	544,654,228	6.94e-05	13	3’	8.20686	8.20686	0	85.1161	85.1161	0				−2.55724	−22.32	1.42

na not available; *Non-Finnish European population based on ExAC database; NM for APC: NM_000038; ATM: NM_000051; AXIN2: NM_004655; BRCA1: NM_007300; CDH1: NM_004360; CDX2: NM_001265; DVL2: NM_004422; MAP3K1: NM_005921; MSH2: NM_000251; MRE11A: NM_005591; MUTYH: NM_012222; NBN: NM_002485; NOTCH3: NM_000435; POLE: NM_006231; PTEN: NM_000314; RAD51B: NM_133509; RAD51D: NM_002878. In order to predict their biological impact, RNA splicing-dedicated bioinformatics analyses were performed as described under Materials and Methods. Results shown in bold were considered as predictive of a potential variant-induced negative biological effect. MES MaxEntScan, SSFL Splice Site Finder-Like, nt Nucleotide, 3′ or 5’ss 3′ splice site or 5′ splice site, ESR Exonic splicing regulators

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ISSN: 1897-4287

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