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. 2021 Sep 30;108(10):1907–1923. doi: 10.1016/j.ajhg.2021.09.003

Table 1.

Variants classified by the COVAR study

Gene Exon/Intron Nucleotide nomenclature Protein nomenclature Prior Probability of pathogenicity Nb of families Family history LR Co-occurrence LR Pathology LR Combined LR without cosegregation IARC 5-tier class without co-segregation dataa Nb of families with co-segregation data Varsome Classb Cosegregation LR Combined LR Posterior Probability of pathogenicity IARC 5-tier class
PATHOGENIC
BRCA1 3 c.121C>T p.His41Tyr 0.81 4 4.88 – 73.42 358.04 – 3 P 128.396 45,970.26 0.9999949 5
BRCA1 I8 c.547+1G>T – 0.97 4 1.87 – 703.797 1,313.41 – 4 P 204.08743 268,050.27 0.99999988 5c
BRCA1 16 c.4963T>G p.Ser1655Ala 0.03 9 1.23 – 19.78 24.36 3 5 LP 93.2268842 2,271.10 0.98596299 4
BRCA1 17 c.4994T>A p.Val1665Glu 0.81 15 5.89 – 41.24 243.08 – 3 LP 53.95 13,114.14 0.99998211 5
BRCA1 17 c.5017_5019del p.His1673del 0.81 6 0.49 – 7.98 3.92 3 3 LP 488.41099 1,914.77 0.99987751 5
BRCA1 17 c.5062G>T p.Val1688Phe 0.03 1 11.69 – 11.79 137.84 3 1 LP 24.025 3,311.52 0.9903305 5
BRCA1 17 c.5072C>T p.Thr1691Ile 0.81 4 3.87 – 23.23 89.99 – 2 P 22.24 2,001.76 0.999882832 5
BRCA1 18 c.5116G>A p.Gly1706Arg 0.81 17 3.17 – 11.79 37.34 – 2 P 61.93 2,312.62 0.99989858 5
BRCA1 18 c.5117G>A p.Gly1706Glu 0.81 10 2.61 – 3.12 8.14 3 4 LP 7.37 59.97 0.99610374 4c
BRCA1 18 c.5144G>A p.Ser1715Asn 0.66 4 6.42 – – 6.42 3 2 P 167.97 1,078.99 0.99952279 5d
BRCA1 18 c.5145C>G p.Ser1715Arg 0.81 3 6.78 – 13.91 94.28 – 2 LP 28.80 2,715.44 0.99991362 5d
BRCA1 20 c.5213G>T p.Gly1738Val 0.81 2 6.05 – 6.21 37.55 – 1 LP 44.08 1,655.39 0.99985832 5
BRCA1 20 c.5216A>G p.Asp1739Gly 0.81 9 0.75 – 1009.26 754.45 – 2 LP 10.57 7,976.71 0.99997059 5
BRCA1 20 c.5216A>T p.Asp1739Val 0.81 5 5.39 – 71.42 384.68 – 3 LP 3.34 1,285.88 0.99981762 5
BRCA1 20 c.5254G>C p.Ala1752Pro 0.03 6 3.80 – 26.97 102.45 3 3 LP 5.88794143 603.24 0.94912744 4
BRCA1 20 c.5255C>A p.Ala1752Glu 0.03 2 10.98 – 10.61 116.44 3 1 LP 14.53517 1,692.47 0.98125391 4
BRCA1 21 c.5309G>Te p.Gly1770Val 0.03 33 2.48 – 5.599E+10 4.66E+12 5 11 P 3,668.96 1.71E+16 0.999999999 5d
BRCA1 21 c.5309_5310delinsTTe p.Gly1770Val 0.03 2 – 5 1 LP 5
BRCA1 23 c.5426T>G p.Val1809Gly 0.66 16 2.36 – 129.20 304.56 – 8 P 60.2 18,334.43 0.9999719 5
BRCA1 23 c.5434C>G p.Pro1812Ala 0.03 12 5.94 – 34.64 205.76 3 5 P 79.1602119 16,288.35 0.99801887 5
BRCA1 24 c.5509T>C p.Trp1837Arg 0.81 3 6.81 – – 6.81 – 2 LP 297.01 2,021.43 0.99988397 5d
BRCA2 3 c.92G>C p.Trp31Ser 0.81 4 2.99 – 3.12 9.31 – 2 P 355.52 3,309.48 0.99992913 5
BRCA2 3 c.68-?_316+?delf p.Asp23_Leu105del 0.5 4 1,381.48 – 15.01 20,737.45 5 1 P 1.42701E+23 2.96E+27 1 5
BRCA2 3 c.156_157insAluf – 0.5 6 0 P 5
BRCA2 I3 c.316+1G>Tf – 0.5 1 0 P 5
BRCA2 I3 c.316+2T>Cf – 0.5 2 0 P 5d
BRCA2 I3 c.316+4delf – 0.5 2 1 LP 5
BRCA2 I3 c.316+5G>Af – 0.5 2 1 LP 5
BRCA2 I3 c.316+5G>Cf – 0.5 28 10 LP 5
BRCA2 16 c.7787G>T p.Gly2596Val 0.5 4 0.27 – 3.35 0.89 3 3 VUS 556.66 497.61 0.99799442 5
BRCA2 16 c.7795_7797delg p.Glu2599del 0.81 101 229.56 – 0.93 212.46 – 14 P 10,545,472.1 2,240,517,687 1 5
BRCA2 17 c.7975A>G p.Arg2659Gly 0.81 22 3.58 – 0.56 2.02 3 14 P 1,114.89 2,253.70 0.99989593 5
BRCA2 18 c.8009C>G p.Ser2670Trp 0.29 12 0.87 – 10.19 8.88 3 5 LP 819.97 7,283.30 0.99966396 5
BRCA2 18 c.8009C>T p.Ser2670Leu 0.29 15 8.47 – 0.87 7.33 3 5 LP 271.63 1,990.34 0.99877143 5
BRCA2 18 c.8057T>C p.Leu2686Pro 0.66 18 2.40 – 54.91 131.96 – 6 VUS 27.92 3,684.35 0.9998602 5
BRCA2 23 c.9004G>A p.Glu3002Lys 0.66 25 1.16 – 7.20 8.36 3 11 P 301.09 2,518.20 0.999795471 5
BRCA2 24 c.9154C>T p.Arg3052Trp 0.81 16 0.99 – 12.07 11.996 – 6 P 102.26 1,820.69 0.99987118 5c
BRCA2 25 c.9371A>T p.Asn3124Ile 0.81 16 1.67 – 8.32 5.40 – 6 P 207.49 2,876.22 0.99991845 5c
BENIGN
BRCA1 3 c.92T>A p.Ile31Asn 0.66 8 0.23 – 0.004 0.0008 2 3 VUS 0.12 9.78E−5 0.000189741 1
BRCA1 6 c.243A>G p.Gln81= 0.02 18 0.03 – 0.3906892 0.0102 – 3 B 2.05213421 0.0209869 0.00042812 1c,d
BRCA1 I6 c.301+6T>C – 0.34 5 1.94 0.001776 0.30 0.01 – 2 VUS 1.6324848 0.00167665 0.00086298 1
BRCA1 10 c.670+8C>T – 0.5 11 0.32 – 0.0006 0.0002 1 4 LB 2.39 0.0005 0.000450112 1
BRCA1 11 c.693G>A p.Thr231= 0.02 20 0.45 – 0.35 0.16 – 3 LB 0.002 0.0003 5.8992E−06 1c
BRCA1 11 c.1065G>A p.Lys355= 0.02 40 1.27 0.006087 0.0008 0.001 1 4 LB 0.09 5.31E−07 1.0831E−08 1c
BRCA1 11 c.1242_1262del p.Asp414_Asp420del 0.02 3 1.82 – 0.08 0.15 3 2 LP 0.09 0.01 0.00027235 1
BRCA1 11 c.1384G>A p.Gly462Arg 0.02 9 0.22 – 0.002 0.0005 1 5 VUS 0.95 0.0005 9.5128E−06 1
BRCA1 11 c.1844C>T p.Ser615Phe 0.03 4 0.19 – 0.21 0.04 – 2 VUS 0.03 0.001 3.735E−05 1
BRCA1 11 c.2083G>T p.Asp695Tyr 0.03 45 0.31 – 0.0003 8.03E−05 1 13 VUS 9.36E−08 7.52E−12 2.325E−13 1
BRCA1 11 c.2662C>T p.His888Tyr 0.03 19 0.55 – 0.0004 0.0002 1 4 VUS 0.008 1.87E−06 5.7872E−08 1
BRCA1 11 c.2798G>A p.Gly933Asp 0.03 9 0.22 – 0.01 0.003 1 2 VUS 3.47 0.01 0.00034753 1
BRCA1 11 c.2884G>A p.Glu962Lys 0.03 9 0.07 – 0.05 0.003 1 2 LB 0.39 0.001 4.1619E−05 1c
BRCA1 11 c.2935C>T p.Arg979Cys 0.02 16 0.31 – 0.0004 0.0001 1 3 VUS 3.22 0.0004 7.6066E−06 1
BRCA1 11 c.3327_3329del p.Lys1110del 0.02 5 0.06 – 0.21 0.012 – 2 LP 0.49 0.006 0.000122496 1
BRCA1 11 c.3708T>G p.Asn1236Lys 0.03 49 0.94 0.008 5.07E−05 4.78E−05 1 9 VUS 0.12 4.51E−08 1.3946E−09 1
BRCA1 11 c.3891_3893del p.Ser1298del 0.02 9 0.24 – 0.05 0.01 1 2 LP 1.28 0.01 0.00028881 1
BRCA1 14 c.4417T>C p.Ser1473Pro 0.03 20 0.14 – 0.003 0.000459893 1 2 VUS 1.195 0.00054971 1.7001E−05 1
BRCA1 I14 c.4485-96A>G – 0.5 4 0.29 – 0.009 0.003 2 3 VUS 0.017 4.26E−05 4.2602E−05 1
BRCA1 17 c.4993G>A p.Val1665Met 0.29 20 0.42 – 0.16 0.07 – 5 LB 0.007 0.00050058 0.00020442 1
BRCA1 17 c.5005G>T p.Ala1669Ser 0.03 7 1.09 – 0.04 0.04 – 3 VUS 0.25 0.01 0.00033277 1
BRCA1 17 c.5071A>G p.Thr1691Ala 0.66 16 1.36 – 0.02 0.02 – 4 LP 0.13 0.003 0.006215 2
BRCA1 18 c.5117G>C p.Gly1706Ala 0.66 76 0.35 – 1.19E−05 4.14E−06 1 12 VUS 1.47E−06 6.09E−12 1.1816E−11 1c
BRCA1 24 c.5531T>C p.Leu1844Pro 0.03 3 0.14 – 1.07 0.15 – 2 VUS 0.0001 1.91E−05 5.9194E−07 1
BRCA1 24 c.5531T>G p.Leu1844Arg 0.03 3 0.15 – 0.002 0.0003 1 2 LB 0.15 4.1067E−05 1.2701E−06 1c
BRCA2 3 c.122C>T p.Pro41Leu 0.03 16 0.40 – 2.77 1.11 3 2 VUS 0.05 0.06 0.001881892 2
BRCA2 3 c.231T>G p.Thr77= 0.01 51 0.49 0.00002 0.79 0.38 1 5 LB 26.95 0.0002 1.7357E−06 1c
BRCA2 5 c.433_435del p.Val145del 0.5 12 0.18 – 0.20 0.04 – 4 VUS 0.02835067 0.0010593 0.00105818 2
BRCA2 10 c.800G>A p.Gly267Glu 0.03 22 0.53 0.006 0.05 0.02 1 6 VUS 5.05 0.0007 2.1713E−05 1
BRCA2 10 c.831T>G p.Asn277Lys 0.02 21 0.42 0.006 0.81 0.34 1 4 VUS 0.03 5.83E−05 1.1898E−06 1
BRCA2 10 c.927A>Gh p.Ser309= 0.02 13 0.12 – 0.33 0.04 – 5 LB 0.18 0.007 0.000150187 1c
BRCA2 10 c.1012G>A p.Ala338Thr 0.03 8 0.02 – 0.58 0.012 – 2 LB 0.33877369 0.00418389 0.00012938 1
BRCA2 10 c.1244A>G p.His415Arg 0.02 7 0.67 – 0.36 0.24 – 2 VUS 0.23 0.06 0.00115238 2
BRCA2 10 c.1564G>C p.Gly522Arg 0.03 9 0.32 – 0.44 0.14040988 – 3 LB 0.04183382 0.00587388 0.00018163 1
BRCA2 10 c.1798T>C p.Tyr600His 0.03 28 0.59 – 0.09 0.05 – 2 LB 0.13 0.007 0.00021097 1
BRCA2 11 c.2771A>T p.Asn924Ile 0.02 29 0.75 – 0.01 0.01 1 9 VUS 0.42 0.004 8.8819E−05 1
BRCA2 11 c.2944A>C p.Ile982Leu 0.03 18 0.50 – 0.099 0.05 – 3 LB 0.01205085 0.00059572 1.8424E−05 1
BRCA2 11 c.3262C>T p.Pro1088Ser 0.02 7 0.83 – – 0.83 – 1 VUS 0.001 0.0008 1.6999E−05 1
BRCA2 11 c.5552T>G p.Ile1851Ser 0.03 13 1.24 – – 1.24 – 7 VUS 0.02 0.02 0.00067659 1
BRCA2 11 c.5634C>G p.Asn1878Lys 0.03 22 0.62 – 0.31 0.19 – 4 VUS 0.03 0.006 0.00017755 1
BRCA2 11 c.5975C>T p.Ser1992Leu 0.29 21 0.28 – 0.53 0.15 3 3 VUS 0.16817314 0.02496567 0.01009431 2
BRCA2 11 c.6322C>T p.Arg2108Cys 0.02 41 0.97 0.00001 0.57 0.55 – 3 LB 5.96 0.03 0.00058336 1
BRCA2 I12 c.6937+594T>G – 0.5 31 0.92 1.78E−8 0.06 1.06E−09 1 12 LB 115.71 1.23E−7 1.2263E−07 1c
BRCA2 14 c.7057G>C p.Gly2353Arg 0.03 11 0.69 – 0.27 0.19 – 4 VUS 0.02 0.003 0.00010507 1
BRCA2 14 c.7219G>C p.Val2407Leu 0.03 5 0.16 – 1.44 0.23 – 3 VUS 0.20491405 0.04770388 0.0014732 2
BRCA2 15 c.7481G>A p.Arg2494Gln 0.66 7 0.19 0.0022 0.51 0.098 – 4 VUS 0.61 0.0001 0.00025681 1
BRCA2 15 c.7504C>T p.Arg2502Cys 0.03 22 0.61 – 0.19 0.12 – 3 LB 0.09 0.01 0.00031486 1
BRCA2 16 c.7759C>Th p.Leu2587Phe 0.29 13 0.12 – 0.33 0.04 – 5 VUS 0.18 0.007 0.0029973 2
BRCA2 17 c.7915C>G p.Pro2639Ala 0.29 6 0.15 – 0.61 0.09 – 3 VUS 0.03 0.003 0.00123378 2
BRCA2 17 c.7928C>G p.Ala2643Gly 0.64 33 0.58 0.0076 0.03 0.02 – 9 VUS 0.01 1.68E−06 2.9926E−06 1
BRCA2 17 c.7933A>G p.Arg2645Gly 0.29 16 0.24 – 0.05 0.01 2 7 VUS 2.93 0.03 0.01329559 2
BRCA2 17 c.7954G>A p.Val2652Met 0.29 27 0.52 0.005 0.76 0.002 1 4 VUS 1.29609452 0.00251463 0.00102605 2
BRCA2 18 c.7992T>A p.Ile2664= 0.02 8 0.82 – 0.35 0.28 – 3 LB 0.00753887 0.00214733 4.3821E−05 1c
BRCA2 18 c.8010G>A p.Ser2670= 0.02 13 0.33 – 1.91 0.62 – 2 LB 0.097 0.06 0.00123121 2c
BRCA2 18 c.8084C>T p.Ser2695Leu 0.03 14 0.43 0.003 0.10 0.0001 – 4 VUS 0.11852903 1.6682E−05 5.1595E−07 1
BRCA2 18 c.8111C>T p.Ser2704Phe 0.03 7 0.64 – 0.13 0.08 – 3 VUS 0.04636364 0.00387602 0.00011986 1
BRCA2 23 c.9104A>C p.Tyr3035Ser 0.66 31 0.64 0.007 0.32 0.20 2 9 VUS 0.33 0.0005 0.00092147 1
BRCA2 23 c.9116C>T p.Pro3039Leu 0.03 24 0.4 – 0.02 0.00754 1 7 VUS 0.55 0.004 0.00012765 1
BRCA2 24 c.9206G>T p.Cys3069Phe 0.03 3 0.07 – 0.59 0.04 – 3 VUS 0.03255207 0.00143349 4.4333E−05 1
BRCA2 25 c.9275A>G p.Tyr3092Cys 0.81 30 0.36 0.008 2.001 0.0056 2 9 VUS 1.44 0.008 0.03490992 2
BRCA2 25 c.9501+3A>T – 0.34 30 0.49 – 0.20 0.09920669 – 7 VUS 0.001 0.0001 7.3072E−05 1
BRCA2 26 c.9583A>G p.Thr3195Ala 0.03 26 0.42 0.005 0.16 0.0003 1 5 LB 0.26 7.6865E−05 2.3773E−06 1
BRCA2 26 c.9606G>C p.Pro3202= 0.02 21 0.40 – 0.04 0.015 – 3 B 0.26 0.0037923 7.7388E−05 1c

Classifications without or with cosegregation data are in bold. See Table S3 for details of ClinVar, BRCAexchange and ACMG classification.

a

Dash (–) means that the posterior probability of pathogenicity was not calculated because the combined LR was not <0.01 or >1,000.

b

This variant was also classified by ACMG using Varsome.

c

This variant was also classified by BRCAexchange.

d

This variant was also classified by ClinVar.

e

BRCA1 variants leading to p.Gly1770Val were combined.

f

BRCA2 variants leading to complete loss of exon were combined.

g

This pathogenic variant probably has a French origin because we find it in many families, particularly in the North of France.

h

Both variants were always observed altogether. Their cosegregation in 4 meiosis supports that they are in cis.