Overall, 63 variants in 17 genes in 61 (13.9%) probands were assessed as P/LP (summary in Table 3; full description with phenotype and previous testing in Table S6). Most were nonsense or frameshift variants. Individuals with variants in moderate-risk CPGs CHEK2 (MIM: 604373; n = 14) and ATM (MIM: 607585; n = 10) were the most frequent; one homozygote was detected for CHEK2: c.1100delC (p.Thr367Metfs) (Ensembl: ENST00000328354; GenBank: NM_007194.3]; annotated in our data as c.1229delC [p.Thr410fs] [Ensembl: ENST00000382580; GenBank: NM_001005735.1]). Individuals with variants in BRCA2 (MIM: 600185; n = 6), PALB2 (MIM: 610355; n = 6), FH (MIM: 136850; n = 5), NF1 (MIM: 613113; n = 4), NTHL1 (MIM: 602656; homozygous, n = 3), MAX (MIM: 154950; n = 2), PTEN (MIM: 601728; n = 2), SDHB (MIM: 185470; n = 2), BMPR1A (MIM: 601299; n = 1), BRCA1 (MIM: 113705; n = 1), CDKN1B (MIM: 600778; n = 1), EXT2 (MIM: 608210; n = 1), MLH1 (MIM: 120436; n = 1), MSH2 (MIM: 609309; n = 1), and PMS2 (MIM: 600259; n = 1) were also noted.
Table 3 Summary of Filtered SNVs and Indels Deemed Pathogenic or Likely Pathogenic by ACMG Assessment
Gene RefSeq mRNA ID No. of Occurrences No. of Individuals with Associated Tumor Variant Description Consequence
ATM GenBank: NM_000051 1 1 c.193C>T (p.Gln65∗) stop gain
ATM GenBank: NM_000051 1 1 c.5623C>T (p.Arg1875∗) stop gain
ATM GenBank: NM_000051 1 0 c.6583+1G>A splice site (donor)
ATM GenBank: NM_000051 1 0 c.6866-6867insT (p.Ser2289Serfs) frameshift
ATM GenBank: NM_000051 1 1 c.748C>T (p.Arg250∗) stop gain
ATM GenBank: NM_000051 1 1 c.8147T>C (p.Val2716Ala) missense
ATM GenBank: NM_000051 1 0 c.8405delA (p.Gln2802fs) frameshift
ATM GenBank: NM_000051 1 0 c.5821G>C (p.Val1941Leu) missense
ATM GenBank: NM_000051 1 0 c.8122G>A (p.Asp2708Asn) missense
ATM GenBank: NM_000051 1 1 c.7775C>G (p.Ser2592Cys) missense
BMPR1Aa GenBank: NM_004329 1 1 c.730C>T (p.Arg244∗) stop gain
BRCA1 GenBank: NM_007300 1 1 c.1961−1962insA (p.Lys654fs) frameshift
BRCA2 GenBank: NM_000059 1 0 c.4525C>T (p.Gln1509∗) stop gain
BRCA2 GenBank: NM_000059 1 1 c.5682C>G (p.Tyr1894∗) stop gain
BRCA2 GenBank: NM_000059 1 0 c.6275−6276delTT (p.Leu2092fs) frameshift
BRCA2 GenBank: NM_000059 1 1 c.6402−6406delTAACT (p.Asn2135Leufs) frameshift
BRCA2 GenBank: NM_000059 1 0 c.6535−6536insA (p.Val2179fs) frameshift
BRCA2 GenBank: NM_000059 1 1 c.1805−1806insA (p.Gly602fs) frameshift
CDKN1B GenBank: NM_004064 1 0 c.148−149delAG (p.Arg50fs) frameshift
CHEK2 GenBank: NM_001005735 3 1 c.1392delT (p.Leu464fs) frameshift
CHEK2 GenBank: NM_001005735 10 6 c.1229delC (p.Thr410fs) frameshift
CHEK2 GenBank: NM_001005735 1 1 c.1051+1C>T splice site (donor)
CHEK2 GenBank: NM_001005735 1 0 c.784delG (p.Glu262fs) frameshift
CHEK2 GenBank: NM_001005735 1 1 c.562C>T (p.Arg188Trp) missense
EXT2 GenBank: NM_000401 1 0 c.613C>T (p.Gln205∗) stop gain
FH GenBank: NM_000143 3 0 c.1433−1434insAAA (p.Lys477_Asn478insLys) in-frame insertion
FH GenBank: NM_000143 1 1 c.320A>C (p.Asn107Thr) missense
FHb GenBank: NM_000143 1 0 c.521C>G (p.Pro174Arg) missense
MAX GenBank: NM_002382 1 1 c.289C>T (p.Gln97∗) stop gain
MAXb GenBank: NM_002382 1 1 c.1A>G (p.Met1Val) start loss
MLH1 GenBank: NM_000249, NM_001258273 1 1 c.1884−1G>A splice site (acceptor)
MSH2 GenBank: NM_000251 1 0 c.1452−1455insAATG (p.Leu484-Met485fs) frameshift
NF1 GenBank: NM_001042492 1 1 c.1541−1542delAG (p.Gln514fs) frameshift
NF1 GenBank: NM_001042492 1 1 c.4620delA (p.Ala1540fs) frameshift
NF1 GenBank: NM_001042492 1 1 c.5831delT (p.Leu1944fs) frameshift
NF1 GenBank: NM_001042492 1 1 c.7768-7769insA (p.His2590fs) frameshift
NTHL1c GenBank: NM_002528 3 3 c.268C>T (p.Gln90∗) stop gain
PALB2 GenBank: NM_024675 4 3 c.3113G>A (p.Trp1038∗) stop gain
PALB2 GenBank: NM_024675 1 1 c.3116delA (p.Asn1039fs) frameshift
PALB2 GenBank: NM_024675 1 1 c.62T>G (p.Leu21∗) stop gain
PMS2a GenBank: NM_000535 1 1 c.741−742insTGAAG (p.Pro247_S248fs) frameshift
PTEN GenBank: NM_000314 1 1 c.1003C>T (p.Arg335∗) stop gain
PTEN GenBank: NM_000314 1 1 c.697C>T (p.Arg233∗) stop gain
SDHB GenBank: NM_003000 1 1 c.223+1C>A splice site (donor)
SDHB GenBank: NM_003000 1 1 c.689G>A (p.Arg230His) missense
This list incorporates one individual per family. See Table S6 for more comprehensive description.
a Occurring in the same individual.
b Occurring in the same individual.
c Homozygous.