1-45329329-T-A

Variant names:

• chr1-45329329-T-A
• NM_001128425.2:c.1627A>T
• MUTYH p.Ser543Cys

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_001048174.2(MUTYH):c.1543A>T (p.Ser515Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S515G: Uncertain_significance (ClinVar VariationId 4113461, 1 star); p.S515I: Uncertain_significance (ClinVar VariationId 4113464, 1 star); p.S515N: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 483902); p.S515R: Uncertain_significance (ClinVar VariationId 4113466, 1 star); p.S515R: Uncertain_significance (ClinVar VariationId 4113465, 1 star); p.S515R: Uncertain_significance (ClinVar VariationId 4113460, 1 star); p.S515= (synonymous): Likely_benign (ClinVar VariationId 702461, 1 star); p.S515T: Uncertain_significance (ClinVar VariationId 4113463, 1 star)

• Frequency: Genomes: not found (cov: 31)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.287
• Publications: 0 publications found

Genes affected

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; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001048174.2. 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
	MUTYH NM_001128425.2	MANE Plus Clinical	c.1627A>T p.Ser543Cys	missense	Exon 16 of 16	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001048174.2	MANE Select	c.1543A>T p.Ser515Cys	missense	Exon 16 of 16	Prot: NP_001041639.1 UniProt:
	MUTYH NM_012222.3		c.1618A>T p.Ser540Cys	missense	Exon 16 of 16	Prot: NP_036354.1 UniProt:

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1627A>Tp.Ser543Cys

Exon rankExon 16 of 16

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1543A>Tp.Ser515Cys

Exon rankExon 16 of 16

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1618A>Tp.Ser540Cys

Exon rankExon 16 of 16

missense

Prot: NP_036354.1UniProt: Q9UIF7-1E5KP26

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MUTYH ENST00000710952.2	MANE Plus Clinical	c.1627A>T p.Ser543Cys	missense	Exon 16 of 16	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000456914.7	TSL:1MANE Select	c.1543A>T p.Ser515Cys	missense	Exon 16 of 16	Prot: ENSP00000407590.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.1618A>T p.Ser540Cys	missense	Exon 16 of 16	Prot: ENSP00000361170.3 UniProt:

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1627A>Tp.Ser543Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1543A>Tp.Ser515Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1618A>Tp.Ser540Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000361170.3UniProt: Q9UIF7-1

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:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.7
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.053	N
FuncVEP CTI	Benign	0.12
GPN-Star LLR	N/A	-1.8
GPN-Star score	N/A	1.8
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.82	T
Mutation Taster	N/A	97/3	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	0.29
popEVE	Benign	-3.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.19
VESM-3B	Benign	-4.0

Showing 28 of 28 scores

Splicing Scores

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

Showing 2 of 2 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

hg19: chr1-45795001;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar