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Table 1 Summary of reclassification for missense MSH2 germline VUS with abnormal LoF scores (n=24), with evidence codes applied for each variant

From: Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome

Variant (in NM_000251.3)

Reclassification outcome

LOF Score (Jia et al. 2021) [26]

MAPP MMR (Chao et al. 2008) [30]

gnomAD frequency

LOF score evidence

Pop. database evidence

Clinical (MSI/IHC)

Computational evidence

Additional evidence

c.2083G>A (p.Val695Met)

Reclassified to LP

4.511

20.15

-

PS3

PM2_P

PP4

  

c.929T>G (p.Leu310Arg)

Reclassified to LP

3.774

33.02

-

PS3

PM2_P

PP4_S

PP3

PP1

c.1568T>C (p.Phe523Ser)

Reclassified to LP

3.547

10.09

-

PS3

PM2_P

PP4

 

PM1

c.443T>A (p.Val148Glu)

Insufficient evidence

3.239

4.13

-

PS3

PM2_P

PP4

  

c.2011A>T (p.Asn671Tyr)

Reclassified to LP

3.114

20.2

-

PS3

PM2_P

PS4_M

PP3

PM1_P

c.1808A>T (p.Asp603Val)

Reclassified to LP

2.999

22.25

-

PS3

PM2_P

PP4

PP3

 

c.1067T>A (p.Ile356Lys)

Reclassified to LP

2.518

14.66

-

PS3

PM2_P

PP4

PP3

 

c.2030C>G (p.Thr677Arg)

Reclassified to LP

2.469

37.76

-

PS3

PM2_P

PP4_M

PP3

PM1

c.2276G>T (p.Gly759Val)

Insufficient evidence

2.215

29.36

-

PS3

PM2_P

 

PP3

 

c.2281G>C (p.Gly761Arg)

Reclassified to LP

2.193

40.89

-

PS3

PM2_P

  

PM1_P

c.2272G>T (p.Asp758Tyr)

Insufficient evidence

1.955

15.52

-

PS3

PM2_P

   

c.2099C>A (p.Ala700Glu)

Reclassified to LP

1.917

37.91

-

PS3

PM2_P

PP4

  

c.2282G>T (p.Gly761Val)

Insufficient evidence

1.785

9.19

-

PS3

PM2_P

   

c.1241T>C (p.Leu414Pro)

Reclassified to LP

1.766

12.66

-

PS3

PM2_P

PP4

 

PM1

c.2768T>A (p.Val923Glu)

Conflicting/insufficient evidence

1.669

n/a

-

PS3_moderatea

PM2_P

BS2_P

  

c.1654A>C (p.Thr552Pro)

Insufficient evidence

1.61

10.84

-

PS3_moderatea

PM2_P

PS4_M

  

c.1601G>C (p.Arg534Pro)

Insufficient evidence

1.383

30.22

-

PS3_moderatea

PM2_P

   

c.1703C>T (p.Thr568Ile)

Conflicting/insufficient evidence

0.932

4.04

-

PS3_moderatea

PM2_P

 

BP4

 

c.1862G>C (p.Arg621Pro)

Insufficient evidence

0.745

30.86

-

PS3_moderatea

PM2_P

PP4

  

c.2272G>C (p.Asp758His)

Insufficient evidence

0.701

18.79

-

PS3_moderatea

PM2_P

   

c.386C>G (p.Ser129Cys)

Conflicting/insufficient evidence

0.574

1.84

2.35E−05

PS3_moderatea

 

PP4

 

BS2_P

c.925G>C (p.Ala309Pro)

Insufficient evidence

0.528

7.68

-

PS3_moderatea

PM2_P

 

PP3

 

c.2132G>T (p.Arg711Leu)

Conflicting/insufficient evidence

0.491

19.03

-

PS3_moderatea

PM2_P

BS2_P

PP3

 

c.1571G>T (p.Arg524Leu)

Insufficient evidence

0.449

17.81

-

PS3_moderatea

PM2_P

   
  1. aPS3_moderate codes are applicable for variants with scores between 0.4 and 1.7, but their reclassification was not pursued here
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Genome Biology

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