1-45340203-C-T

Variant names:

• chr1-45340203-C-T
• rs748512468
• NM_025077.4:c.-50C>T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_001407071.1(MUTYH):c.-7G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. Note: NM_001407071.1 is not a MANE Select or MANE Plus Clinical transcript for MUTYH; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The gene MUTYH is a cancer driver gene (CancerMine: 2 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (AlphaMissense) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001407071.1 splice_region
• Scores: Splicing: ADA: 0.4015
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Jul 2025]

TOE1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 7

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Splice-region variant — splicing algorithms predict no impact on splicing; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001407071.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 NM_025077.4	MANE Select	c.-50C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	Prot: NP_079353.3
	TOE1 NM_025077.4	MANE Select	c.-50C>T	5_prime_UTR	Exon 1 of 8	Prot: NP_079353.3
	MUTYH NM_001128425.2	MANE Plus Clinical	c.36+16G>A	intron	Intron 1 of 15	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001407071.1		c.-7G>A	splice_region	Exon 1 of 16	Prot: NP_001394000.1 UniProt:
	MUTYH NM_001407070.1		c.-7G>A	splice_region	Exon 1 of 16	Prot: NP_001393999.1 UniProt:
	MUTYH NM_001407071.1		c.-7G>A	5_prime_UTR	Exon 1 of 16	Prot: NP_001394000.1 UniProt:
	MUTYH NM_001407070.1		c.-7G>A	5_prime_UTR	Exon 1 of 16	Prot: NP_001393999.1 UniProt:
	MUTYH NM_012222.3		c.36+16G>A	intron	Intron 1 of 15	Prot: NP_036354.1 UniProt:
	MUTYH NM_001293190.2		c.36+16G>A	intron	Intron 1 of 15	Prot: NP_001280119.1 UniProt:
	MUTYH NM_001407069.1		c.36+16G>A	intron	Intron 1 of 14	Prot: NP_001393998.1
	MUTYH NM_001048171.2		c.-7+16G>A	intron	Intron 1 of 15	Prot: NP_001041636.2 UniProt:
	MUTYH NM_001407072.1		c.-7+20G>A	intron	Intron 1 of 15	Prot: NP_001394001.1 UniProt:
	MUTYH NM_001407073.1		c.36+16G>A	intron	Intron 1 of 14	Prot: NP_001394002.1
	MUTYH NM_001293192.2		c.-219+16G>A	intron	Intron 1 of 15	Prot: NP_001280121.1
	MUTYH NM_001350650.2		c.-278+16G>A	intron	Intron 1 of 14	Prot: NP_001337579.1
	MUTYH NM_001350651.2		c.-214+16G>A	intron	Intron 1 of 14	Prot: NP_001337580.1
	MUTYH NR_146882.2		n.222+16G>A	intron	Intron 1 of 16	Prot:
	MUTYH NR_176269.1		n.218+20G>A	intron	Intron 1 of 16	Prot:
	MUTYH NR_176274.1		n.222+16G>A	intron	Intron 1 of 16	Prot:
	MUTYH NM_001048174.2	MANE Select	c.-311G>A	upstream_gene	N/A	Prot: NP_001041639.1 UniProt:
	MUTYH NM_001407083.1		c.-234G>A	upstream_gene	N/A	Prot: NP_001394012.1 UniProt:
	MUTYH NM_001407085.1		c.-311G>A	upstream_gene	N/A	Prot: NP_001394014.1 UniProt:
	MUTYH NM_001293191.2		c.-311G>A	upstream_gene	N/A	Prot: NP_001280120.1 UniProt:
	MUTYH NM_001407077.1		c.-234G>A	upstream_gene	N/A	Prot: NP_001394006.1 UniProt:
	MUTYH NM_001407087.1		c.-764G>A	upstream_gene	N/A	Prot: NP_001394016.1 UniProt:
	MUTYH NM_001048172.2		c.-234G>A	upstream_gene	N/A	Prot: NP_001041637.1 UniProt:
	MUTYH NM_001407078.1		c.-384G>A	upstream_gene	N/A	Prot: NP_001394007.1 UniProt:
	MUTYH NM_001407086.1		c.-311G>A	upstream_gene	N/A	Prot: NP_001394015.1 UniProt:
	MUTYH NM_001048173.2		c.-234G>A	upstream_gene	N/A	Prot: NP_001041638.1 UniProt:
	MUTYH NM_001293195.2		c.-461G>A	upstream_gene	N/A	Prot: NP_001280124.1 UniProt:
	MUTYH NM_001407081.1		c.-384G>A	upstream_gene	N/A	Prot: NP_001394010.1 UniProt:
	MUTYH NM_001407088.1		c.-452G>A	upstream_gene	N/A	Prot: NP_001394017.1 UniProt:
	MUTYH NM_001407089.1		c.-548G>A	upstream_gene	N/A	Prot: NP_001394018.1 UniProt:
	MUTYH NM_001407079.1		c.-234G>A	upstream_gene	N/A	Prot: NP_001394008.1
	MUTYH NM_001407080.1		c.-234G>A	upstream_gene	N/A	Prot: NP_001394009.1
	MUTYH NM_001407075.1		c.-390G>A	upstream_gene	N/A	Prot: NP_001394004.1
	MUTYH NM_001293196.2		c.-446G>A	upstream_gene	N/A	Prot: NP_001280125.1
	MUTYH NM_001407091.1		c.-523G>A	upstream_gene	N/A	Prot: NP_001394020.1
	MUTYH NM_001407082.1		c.-441G>A	upstream_gene	N/A	Prot: NP_001394011.1
	MUTYH NR_146883.2		n.-83G>A	upstream_gene	N/A	Prot:
	MUTYH NR_176271.1		n.-83G>A	upstream_gene	N/A	Prot:
	MUTYH NR_176272.1		n.-83G>A	upstream_gene	N/A	Prot:
	MUTYH NR_176273.1		n.-83G>A	upstream_gene	N/A	Prot:

TOE1 NM_025077.4

MANE Select

HGVSc / HGVSpc.-50C>T

Exon rankExon 1 of 8

5_prime_UTR_premature_start_codon_gain

Prot: NP_079353.3

TOE1 NM_025077.4

MANE Select

HGVSc / HGVSpc.-50C>T

Exon rankExon 1 of 8

5_prime_UTR

Prot: NP_079353.3

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 15

intron

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001407071.1

HGVSc / HGVSpc.-7G>A

Exon rankExon 1 of 16

splice_region

Prot: NP_001394000.1UniProt: Q9UIF7-5E5KP28

MUTYH NM_001407070.1

HGVSc / HGVSpc.-7G>A

Exon rankExon 1 of 16

splice_region

Prot: NP_001393999.1UniProt: Q9UIF7-6

MUTYH NM_001407071.1

HGVSc / HGVSpc.-7G>A

Exon rankExon 1 of 16

5_prime_UTR

Prot: NP_001394000.1UniProt: Q9UIF7-5E5KP28

MUTYH NM_001407070.1

HGVSc / HGVSpc.-7G>A

Exon rankExon 1 of 16

5_prime_UTR

Prot: NP_001393999.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 15

intron

Prot: NP_036354.1UniProt: Q9UIF7-1E5KP26

MUTYH NM_001293190.2

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 15

intron

Prot: NP_001280119.1UniProt: Q9UIF7-2

MUTYH NM_001407069.1

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 14

intron

Prot: NP_001393998.1

MUTYH NM_001048171.2

HGVSc / HGVSpc.-7+16G>A

Exon rankIntron 1 of 15

intron

Prot: NP_001041636.2UniProt: E5KP27Q9UIF7-6

MUTYH NM_001407072.1

HGVSc / HGVSpc.-7+20G>A

Exon rankIntron 1 of 15

intron

Prot: NP_001394001.1UniProt: Q9UIF7-6

MUTYH NM_001407073.1

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 14

intron

Prot: NP_001394002.1

MUTYH NM_001293192.2

HGVSc / HGVSpc.-219+16G>A

Exon rankIntron 1 of 15

intron

Prot: NP_001280121.1

MUTYH NM_001350650.2

HGVSc / HGVSpc.-278+16G>A

Exon rankIntron 1 of 14

intron

Prot: NP_001337579.1

MUTYH NM_001350651.2

HGVSc / HGVSpc.-214+16G>A

Exon rankIntron 1 of 14

intron

Prot: NP_001337580.1

MUTYH NR_146882.2

HGVSc / HGVSpn.222+16G>A

Exon rankIntron 1 of 16

intron

Prot:

MUTYH NR_176269.1

HGVSc / HGVSpn.218+20G>A

Exon rankIntron 1 of 16

intron

Prot:

MUTYH NR_176274.1

HGVSc / HGVSpn.222+16G>A

Exon rankIntron 1 of 16

intron

Prot:

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.-311G>A

Exon rankN/A

upstream_gene

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_001407083.1

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001394012.1UniProt: E9PM53

MUTYH NM_001407085.1

HGVSc / HGVSpc.-311G>A

Exon rankN/A

upstream_gene

Prot: NP_001394014.1UniProt: E9PM53

MUTYH NM_001293191.2

HGVSc / HGVSpc.-311G>A

Exon rankN/A

upstream_gene

Prot: NP_001280120.1UniProt: Q9UIF7-4

MUTYH NM_001407077.1

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001394006.1UniProt: Q9UIF7-4

MUTYH NM_001407087.1

HGVSc / HGVSpc.-764G>A

Exon rankN/A

upstream_gene

Prot: NP_001394016.1UniProt: A0AAQ5BGW7

MUTYH NM_001048172.2

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001041637.1UniProt: E5KP28Q9UIF7-5

MUTYH NM_001407078.1

HGVSc / HGVSpc.-384G>A

Exon rankN/A

upstream_gene

Prot: NP_001394007.1UniProt: Q9UIF7-5E5KP28

MUTYH NM_001407086.1

HGVSc / HGVSpc.-311G>A

Exon rankN/A

upstream_gene

Prot: NP_001394015.1UniProt: Q9UIF7-5E5KP28

MUTYH NM_001048173.2

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001041638.1UniProt: Q9UIF7-6

MUTYH NM_001293195.2

HGVSc / HGVSpc.-461G>A

Exon rankN/A

upstream_gene

Prot: NP_001280124.1UniProt: Q9UIF7-6

MUTYH NM_001407081.1

HGVSc / HGVSpc.-384G>A

Exon rankN/A

upstream_gene

Prot: NP_001394010.1UniProt: Q9UIF7-6

MUTYH NM_001407088.1

HGVSc / HGVSpc.-452G>A

Exon rankN/A

upstream_gene

Prot: NP_001394017.1UniProt: Q9UIF7-6

MUTYH NM_001407089.1

HGVSc / HGVSpc.-548G>A

Exon rankN/A

upstream_gene

Prot: NP_001394018.1UniProt: Q9UIF7-6

MUTYH NM_001407079.1

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001394008.1

MUTYH NM_001407080.1

HGVSc / HGVSpc.-234G>A

Exon rankN/A

upstream_gene

Prot: NP_001394009.1

MUTYH NM_001407075.1

HGVSc / HGVSpc.-390G>A

Exon rankN/A

upstream_gene

Prot: NP_001394004.1

MUTYH NM_001293196.2

HGVSc / HGVSpc.-446G>A

Exon rankN/A

upstream_gene

Prot: NP_001280125.1

MUTYH NM_001407091.1

HGVSc / HGVSpc.-523G>A

Exon rankN/A

upstream_gene

Prot: NP_001394020.1

MUTYH NM_001407082.1

HGVSc / HGVSpc.-441G>A

Exon rankN/A

upstream_gene

Prot: NP_001394011.1

MUTYH NR_146883.2

HGVSc / HGVSpn.-83G>A

Exon rankN/A

upstream_gene

Prot:

MUTYH NR_176271.1

HGVSc / HGVSpn.-83G>A

Exon rankN/A

upstream_gene

Prot:

MUTYH NR_176272.1

HGVSc / HGVSpn.-83G>A

Exon rankN/A

upstream_gene

Prot:

MUTYH NR_176273.1

HGVSc / HGVSpn.-83G>A

Exon rankN/A

upstream_gene

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 ENST00000372090.6	TSL:1MANE Select	c.-50C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	Prot: ENSP00000361162.5 UniProt:
	TOE1 ENST00000372090.6	TSL:1MANE Select	c.-50C>T	5_prime_UTR	Exon 1 of 8	Prot: ENSP00000361162.5 UniProt:
	MUTYH ENST00000710952.2	MANE Plus Clinical	c.36+16G>A	intron	Intron 1 of 15	Prot: ENSP00000518552.2 UniProt:

TOE1 ENST00000372090.6

TSL:1MANE Select

HGVSc / HGVSpc.-50C>T

Exon rankExon 1 of 8

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000361162.5UniProt: Q96GM8-1

TOE1 ENST00000372090.6

TSL:1MANE Select

HGVSc / HGVSpc.-50C>T

Exon rankExon 1 of 8

5_prime_UTR

Prot: ENSP00000361162.5UniProt: Q96GM8-1

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.36+16G>A

Exon rankIntron 1 of 15

intron

Prot: ENSP00000518552.2UniProt: E5KP25

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Benign	0.18
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.94
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
PhyloP100	Benign	1.3
PromoterAI	N/A	0.080	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.49
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs748512468;

hg19: chr1-45805875;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar