Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

Mur, Pilar; Viana-Errasti, Julen; García-Mulero, Sandra; Magraner-Pardo, Lorena; Muñoz, Inés G.; Pons, Tirso; Capellá, Gabriel; Pineda, Marta; Feliubadaló, Lidia; Valle, Laura

doi:10.1186/s13073-023-01234-y

Table 2 Germline POLE and POLD1 ED variants reported in the literature with strong evidence to be considered (likely) pathogenic or (likely) benign. The criteria considered for their selection as pathogenic or benign (criteria in Table 1) are highlighted in bold. Details and references are shown in Table S3

From: Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

Variant	MAF^a	Exo motif / Exonuclease catalytic site / DNA binding^b	REVEL^c	Somatic hotspot^d or recurrent in PPAP^e	CMMRD-like phenotype	No. tumors with SBS10, 14, &/or 20 vs. total no. tumors^f
Pathogenic
POLE:c.824A>T; p.Asp275Val	0	Exo I-catalytic (BLOSUM62: -3)	0.817	No	No	n.a
POLE:c.830A>G; p.Glu277Gly	0	Exo I-catalytic (BLOSUM62: -2) < 6 Å from DNA	0.835	No	CMMRD-like	n.a
POLE:c.833C>A; p.Thr278Lys	0	Exo I < 6 Å from DNA	0.666	No	No	6/6
POLE:c.857C>G; p.Pro286Arg	0	Flanking Exo I < 6 Å from DNA	0.837	Somatic hotspot (n = 86 tumors)	No	28/28
POLE:c.881T>G; p.Met294Arg	0	Flanking Exo I < 6 Å from DNA	0.815	Recurrent in PPAP (n = 3 families)	No	2/3
POLE:c.890C>T; p.Ser297Phe	0	Outside Exo	0.799	Somatic hotspot (n = 17 tumors)	CMMRD-like ≥ 1 de novo	5/5
POLE:c.1089C>G; p.Asn363Lys	0	Exo II < 6 Å from DNA	0.735	Recurrent in PPAP (n = 3 families) ≥ 1 de novo	No	1/1
POLE:c.1231G>C; p.Val411Leu	0	Flanking Exo IV	0.457	Somatic hotspot (n = 73 tumors)	CMMRD-like ≥ 1 de novo	23/23
POLE:c.1270C>G; p.Leu424Val	0	Exo IV < 6 Å from DNA	0.654	Recurrent in PPAP (n = 24 families) ≥ 1 de novo	No	7/7
POLE:c.1307C>G; p.Pro436Arg	0	Exo V	0.592	No	CMMRD-like	2/2
POLE:c.1331T>A p.Met444Lys	0	Flanking Exo V < 6 Å from DNA	0.621	No	CMMRD-like	2/2
POLE:c.1366G >C; p.Ala456Pro	0	Exo III	0.620	Somatic hotspot (n = 19 tumors)	CMMRD-like	5/5
POLE:c.1381T>A; p.Ser461Thr	0	Exo III	0.587	No	CMMRD-like ≥ 1 de novo	2/2
POLD1:c.947A>G; p.Asp316Gly	0	Exo I-catalytic (BLOSUM62: -1) < 6 Å from DNA	0.773	No	No	0/1 (somatic dMMR)
POLD1:c.946G>C; p.Asp316His	1/231076 (0.0004%)	Exo I-catalytic (BLOSUM62: -1) < 6 Å from DNA	0.743	No	No	1/1 and POLD1 cnLOH (germline, pMMR)
POLD1:c.1421T >C; p.Leu474Pro	0	Exo IV < 6 Å from DNA	0.913	Recurrent in PPAP (n = 5 families)	No	1/1 and POLD1 cnLOH (germline, pMMR)
POLD1:c.1433G>A; p.Ser478Asn	0	Exo IV	0.377	Recurrent in PPAP (n = 6 families)	No	1/1 (somatic, dMMR) 7/7 (germline, pMMR) 1/1 and POLD1 cnLOH (germline, pMMR)
Benign
POLE:c.861T >A; p.Asp287Glu	216/268316 (0.08%)	Flanking Exo I	0.286	No (families with no PPAP phenotype)	No	0/2
POLE:c.1007A>G; p.Asn336Ser	702/263956 (0.26%); 11 homoz	outside	0.425	No	No	n.a
POLE:c.1145G>A; p.Ser382Asn	33/236892 (0.014%); 2 homoz (0.1% in Asians)	outside	0.055	No (only present in gnomAD individuals)	No	n.a
POLD1:c.1504G>A; p.Asp502Asn	52/256992 (0.020%)	Flanking Exo III	0.132	No (only present in gnomAD individuals)	No	n.a
POLD1:c.1562G>A; p.Arg521Gln	31/267602 (0.012%) (0.024% in NFE)	outside	0.278	No	No	0/1

Abbreviations: CMMRD constitutional mismatch repair deficiency, dMMR MMR deficiency, homoz homozygotes, MAF minor allele frequency, MMR mismatch repair, n.a. not available information, NFE non-Finnish Europeans, pMMR MMR proficiency, PPAP polymerase proofreading-associated polyposis
^aPopulation MAF: GnomAD v.2.1.1, non-cancer individuals. MAF = 0 was considered when the variant was not reported in gnomAD but was in a region covered by the sequencing data (> 30X coverage) [59]
^bExo Motifs (I – V): POLE: Exo I, amino acids (aa.) 271–285; Exo II, aa. 359–372; Exo III, aa. 453–466; Exo IV, aa. 420–428; Exo V, aa. 430–438. POLD1: Exo I, aa. 312–326; Exo II, aa. 393–406; Exo III, aa. 506–519; Exo IV, aa. 470–478; Exo V, aa. 485–493). Exonuclease catalytic sites: POLE D275 and E277, and POLD1 D316 and E318. For DNA binding information, see Material and Methods for details and definitions, and Table S2 for specific values (predictions)
^cREVEL score: 0–1; the closer to one, the higher pathogenicity prediction
^dA variant was considered a somatic hotspot when present in ≥ 10 tumors (TCGA and COSMIC data considered; Table S5)
^eA germline variant was considered recurrent in PPAP families when present in ≥ 3 PPAP-affected families
^fTumors from TCGA and COSMIC with available exome sequencing data, and tumors from hereditary cases with available mutational signature information reported in the literature, were considered

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