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Table 4 Missense and splice variants of unknown significance detected by NGS-based sequencing

From: Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Gene (transcript GRCh37/hg19) Index patient identifier Variant type Exons/total no. of exons cDNA change Predicted amino acid change dbSNP Total allele frequency, gnomAD; population with highest AFa In silico predictionb Splicing predictions at nearest natural junction
ALK (NM_004304.4) 52 Splice region and synonymous 17/29 c.2817C>T p.(Gly939Gly) rs112022466 0.0001840; SA: 0.0006173   Native acceptor site:
MaxEnt: + 23.7%
NNSPLICE: + 9.5%
HSF: + 0.9%
GeneSplicer: + 32.0%
APC (NM_001127510.2) 83 Missense 17/17 c.4918C>T p.(Arg1640Trp) rs373440614 0.00007223; C  
O: 0.0001548  
ATM (NM_000051.3) 20 Missense 10/63 c.1271C>A p.(Pro424His) rs147472613 0.00002188; D  
A: 0.00004189
ATM (NM_000051.3) 20 Missense 50/63 c.7357C>T p.(Arg2453Cys) rs755418571 0.00001219; C  
EA: 0.00005807
BRCA2 (NM_000059.3) 36 Missense 10/27 c.831T>G p.(Asn277Lys) rs28897705 0.00006632; B  
NFE: 0.0001440
BRCA2 (NM_000059.3) 30 Missense 11/27 c.6101G>A p.(Arg2034His) rs80358849 0.000004069; B  
NFE: 0.000008973
BRCA2 (NM_000059.3) 80 Missense 14/27 c.7021C>T p.(Arg2341Cys) rs41293505 0.00002439; D  
EA: 0.00005798
BRIP1 (NM_032043.2) 68 Missense 15/20 c.2220G>T p.(Gln740His) rs45589637 0.0005198; B  
L: 0.001395
CHEK2 (NM_007194.3 79 Missense 4/15 c.539G>A p.(Arg180His) rs137853009 0.00006494; C  
L: 0.0002615
CHEK2 (NM_007194.3) 83 Missense 6/15 c.688G>C p.(Ala230Pro) rs748636216 0.000004063; D  
NFE: 0.000008956
DDB2 (NM_000107.2) 23 Missense 7/10 c.947C>T p.(Ser316Phe) rs375788966 0.00001218; C  
SA: 0.00003249
DICER1 (NM_030621.4) 8 Missense 25/29 c.4228A>T p.(Asn1410Tyr)   not found D  
DIS3L2 (NM_152383.4) 65 Missense 20/21 c.2450C>T p.(Thr817Met) rs376816858 0.00006697; C  
SA: 0.0003505
EGFR (NM_005228.3) 54 Missense 17/28 c.2039G>A p.(Arg680Gln) rs373336251 0.00009084; D  
FE: 0.0003912
ERCC2 (NM_000400.3) 24 Disruptive inframe deletion 20/23 c.1857_1859delCAT p.(Ile619del)   0.000008127;   
EA: 0.00005800
ERCC2 (NM_000400.3) 55 Missense 22/23 c.2083C>T p.(Arg695Cys) rs201392911 0.0001372; D  
A: 0.0003331
ERCC4 (NM_005236.2) 23 Missense 11/11 c.2395C>T p.(Arg799Trp) rs121913049 0.0004476; D  
NFE: 0.0008138
ERCC5 (NM_000123.3) 23 Missense 1/15 c.56C>T p.(Pro19Leu) rs34291397 0.0005702; C  
NFE: 0.001092
ERCC5 (NM_000123.3) 76 Missense 13/15 c.2818G>A p.(Val940Met) rs146344855 0.0009378; C  
AJ: 0.005122
EXT2 (NM_000401.3) 13 Missense 6/14 c.1064G>A p.(Arg355His) rs149727518 0.0006422; D  
AJ: 0.003448
EXT2 (NM_000401.3) 54 Missense 7/14 c.1186G>A p.(Val396Met) rs138943091 0.0004148; D  
NFE: 0.0007261
FANCA (NM_000135.2) 41, 73 Missense 1/43 c.64T>G p.(Trp22Gly)   not found D  
FANCA (NM_000135.2) 8 Missense 16/43 c.1489C>G p.(Pro497Ala)   not found D  
FANCA (NM_000135.2) 27 Missense 22/43 c.2000C > G p.(Pro667Arg) rs755293596 0.00002230; D  
SA: 0.00004382
FANCA (NM_000135.2) 49 Missense 35/43 c.3430C>T p.(Arg1144Trp) rs143671872 0.0005269; D  
NFE: 0.0009237   
FANCA (NM_000135.2) 54 Missense 37/43 c.3688C>G p.(Leu1230Val) rs576401459 0.00002030; D  
A: 0.00006535
FANCD2 (NM_033084.3) 57 Missense 21/43 c.1933G>T p.(Asp645Tyr) rs146496253 0.0001371; C  
NFE: 0.0002288
FANCI (NM_001113378.1) 35 Missense 17/38 c.1589T>C p.(Leu530Pro) rs766346156 0.000008122; D  
SA: 0.00006497
GPC3 (NM_001164617.1) 19 Missense 8/9 c.1630C>T p.(Arg544Cys) rs759543703 0.00009270; D  
A: 0.0001707
HNF1A (NM_000545.6) 48 Missense 5/10 c.1061C>T p.(Thr354Met) rs757068809 0.00006495; D  
L: 0.0001743
KIT (NM_000222.2) 39 Missense 3/21 c.391G>A p.(Asp131Asn)   0.00001807; C  
A: 0.00004164
MET (NM_001127500.1) 13 Missense 2/21 c.1076G>A p.(Arg359Gln) rs201274041 0.0002347; D  
NFE: 0.0004298
MET (NM_001127500.1) 75 Missense 14/21 c.3023G>A p.(Ser1008Asn)   not found D  
MLH1 (NM_000249.3) 51 Missense 13/19 c.1457C>T p.(Ser486Phe) rs532873141 0.000004061; C  
EA: 0.00005798
NF1 (NM_001042492) 28 Missense 5/58 c.575G>A p.(Arg192Gln) rs587781670 0.00005294; C  
EA: 0.0005803
NSD1 (NM_022455.4) 10 Missense 23/23 c.7352G>A p.(Arg2451Lys) rs200115665 0.0001119; D  
NFE: 0.0002212
PALB2 (NM_024675.3) 56 Missense 8/13 c.2792T>G p.(Leu931Arg) rs773831304 0.00001221; D  
NFE: 0.00002694
PMS1 (NM_000534.4) 67 Missense 2/13 c.118G>C p.(Val40Leu)   not found B  
PMS1 (NM_000534.4) 12 Missense 3/13 c.287C>A p.(Ala96Asp) rs139414606 0.000004063; D  
NFE: 0.000008962
PTCH1 (NM_001083602.1) 4 Missense 23/24 c.3749A>G p.(Tyr1250Cys) rs147067171 0.0005463; D  
AJ: 0.001098
RAD51C (NM_058216.2) 42 Splice region 8/8 c.1026+5_1026+7 delGTA   rs747311993 0.00001219;   Native donor site:
SSF: − 100.0%
MaxEnt: − 100.0%
NNSPLICE: − 99.6%
HSF: − 14.8%
NFE: 0.00002687
RAD51D (NM_002878.3) 52 Missense 5/10 c.355T>C p.(Cys119Arg) rs201313861 0.00005413; B  
L: 0.00008716
RHBDF2 (NM_024599.5) 3, 75 Missense 8/19 c.940G>A p.(Ala314Thr) rs140433374 0.0007812; C  
FE: 0.001173
SDHB (NM_003000.2) 81 Missense 2/8 c.178A>G p.(Thr60Ala) rs34599281 0.00006095; D  
NFE: 0.0001165
SLX4 (NM_032444.2) 14 Missense 14/15 c.4831G>A p.(Glu1611Lys) rs766110479 0.00002847; D  
EA: 0.00005798
TSC1 (NM_000368.4) 51 Missense 12/23 c.1178C>T p.(Thr393Ile) rs201452238 0.00002170; D  
A: 0.00004165
TSC2 (NM_000548.4) 32 Missense 36/42 c.4582G>C p.(Glu1528Gln)   not found D  
WRN (NM_000553.4) 55 Missense 19/35 c.2131C>T p.(Arg711Trp) rs34560788 0.0002057; D  
NFE: 0.0003948
  1. Abbreviations: HSF Human Splicing Finder, SSF Splice Site Finder
  2. aNFE European (non-Finnish), FE European (Finnish), A African, L Latino, EA East Asian, SA South Asian, AJ Ashkenazi Jewish, O Other
  3. bBased on in silico prediction tools Align GVGD, MetaLR, SIFT, and Polymorphism Phenotyping version 2 (PolyPhen-2) (HDIV), as well as phyloP basewise conservation scores; rated as probably damaging (D) with at least 3 of 5 tools predicting damage; rated as probably benign (B) with at least 4 of 5 tools predicting tolerance; or rated as contradictory (C) with 2 of 5 tools predicting damage or conflicting results