Table 1 Participants categorized into the potential MUTYH biallelic group, based on either carrying a germline pathogenic variant and one or more VUSs, or multiple VUSs.

From: Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

ID	AgeDx	Sex	Source	MUTYH variants	ClinVar	GnomAD	CADD	REVEL	SBS18/36 (%)	Error (%)	Somatic mutations	TMS-based prediction	Variant reclassification
C2904	70–79	F	Germline Germline	c.91delG p.A31PfsTer27 c.1141G>T p.G381W	PV VUS	None None	23.0 23.8	None 0.521	62	38.1	15	Positive	VUS->PV
O1016	40–49	F	Germline Germline	c.536A>G p.Y179C c.577-5A>G	PV VUS	0.001 None	24.7 16.9	0.963 None	56.1	17.1	14	Positive	VUS->PV
C5024	50–59	M	Germline Germline Germline	c.536A>G p.Y179C c.933+3A>C c.1465G>A p.A489T	PV VUS VUS	1.5 × 10⁻³ 6.5 × 10⁻⁵ 6.5 × 10⁻⁵	24.7 6.4 29.4	0.963 None 0.724	76.7	17.1	26	Positive	None
C0302	60–69	M	Germline Germline	c.1187G>A p.G396D c.1276C>T p.R426C	PV VUS	0.003 0.001	29.4 22.9	0.551 0.615	46.7	23.9	11	Negative	VUS->Benign
C4622	40–49	M	Germline Germline	c.1187G>A p.G396D c.912C>G p.S304R	PV VUS	0.003 3 × 10⁻⁵	29.4 12.8	0.551 0.229	26.4	45.4	9	Negative	VUS->Benign
O1569	30–39	F	Germline Germline	c.1187G>A p.G396D c.821G>A p.R274Q	PV VUS	0.003 0.0002	29.4 33	0.551 0.229	24.9	45.8	10	Negative	VUS->Benign
C5299	40–49	M	Germline Somatic	c.1187G>A p.G396D c.1596C>A p.F532L	PV VUS	0.003 2.8 × 10⁻⁵	29.4 12.3	0.551 0.063	8.7	1.5	175	Negative	None
C4551	40–49	F	Germline Somatic	c.389-1G>A c.926G>A p.R309H	PV VUS	1.2 × 10⁻⁵ 0.0005	2.3 13.9	0.592 0.293	0	3.6	120	Negative	None
O0497	70–79	F	Germline Somatic	c.1187G>A p.G396D c.607C>T p.R203C	PV VUS	0.003 3.7 × 10⁻⁵	29.4 23.9	0.551 0.358	0	4.6	19	Negative	None
C1060	70–79	M	Germline Germline	c.1465G>A p.A489T c.933+3A>C	VUS VUS	6.5 × 10⁻⁵ 6.5 × 10⁻⁵	6.4 29.4	None 0.724	0	50.3	4	Negative	None
O2193	60–69	F	Germline Germline	c.1431G>C p.T477T c.932G>A p.R311K	VUS VUS	0.006 2.6 × 10⁻⁴	4.6 5.3	0.039 0.24	53	54.7	9	Negative	None
O3288	80–89	F	Germline Germline	c.1420C>T p.R474C c.603G>T p.M201I	VUS VUS	3.2 × 10⁻⁵ None	23.2 16.8	0.546 0.262	9.9	41.7	10	Negative	None
O3593	60–69	F	Germline Germline	c.1276C>T p.R426C c.389-13C>G	VUS VUS	0.001 6.5E−5	22.9 14.9	0.615 None	9	10.7	251	Negative	None
O1434	60–69	M	Germline	c.925C>T p.R309C (H)	VUS	5.4 × 10⁻⁴	13.90	0.592	0.9	25.8	14	Negative	VUS->Benign
O3484	30–39	M	Germline	c.925C>T p.R309C (H)	VUS	5.5 × 10⁻⁴	13.90	0.592	0	39.4	4	Negative	VUS->Benign
C1701	30–39	F	Germline Germline Germline Germline	c.1431G>C p.T477T (H) c.74G>A p.G25D c.53C>T p.P18L c.165+37_1650+39delGTT	VUS VUS VUS VUS	0.006 1.1 × 10⁻³ 1.1 × 10⁻³ None	4.6 14.2 16.7 12.8	0.039 0.111 0.2 None	51.6	39.8	6	Negative	VUS->Benign
O3625	70–79	M	Somatic Somatic	c.1286G>T p.G429V c.404T>A p.V135D	None None	None None	22.3 28.9	0.658 0.898	3.2	6.6	86	Negative	None

The characteristics of participants and each of the variants identified including ClinVar classification, CADD and REVEL prediction scores, and gnomAD allele frequency, as well as the features of the optimized classifier: SBS18 + SBS36 (>51% for positivity), TMS reconstruction error (<39% for positivity), and somatic mutation count (≥9 for positivity) and the TMS-based pathogenicity prediction (positive for biallelic inactivation, negative for no biallelic inactivation). We indicate the seven VUSs that the classifier provides evidence for reclassification as either likely pathogenic or likely benign. AgeDx age of diagnosis, PV pathogenic variant, TMS tumor mutational signature, VUS variant of uncertain significance, (H) homozygous for germline variant; CADD score >20.0 or REVEL score >0.6 considered predicted pathogenic.

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Table 1 Participants categorized into the potential MUTYH biallelic group, based on either carrying a germline pathogenic variant and one or more VUSs, or multiple VUSs.

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