1-45331448-G-T

Variant names:

• chr1-45331448-G-T
• rs1276625381
• NM_001128425.2:c.1295C>A
• MUTYH p.Pro432Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001048174.2(MUTYH):c.1211C>A (p.Pro404Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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.P404A: Uncertain_significance (ClinVar VariationId 4113156, 1 star); p.P404L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2740970); p.P404= (synonymous): Likely_benign (ClinVar VariationId 4860472, 1 star); p.P404R: Uncertain_significance (ClinVar VariationId 4113157, 1 star)

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.833
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00473) — PM2 moderate.

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.1295C>A p.Pro432Gln	missense	Exon 13 of 16	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001048174.2	MANE Select	c.1211C>A p.Pro404Gln	missense	Exon 13 of 16	Prot: NP_001041639.1 UniProt:
	MUTYH NM_012222.3		c.1286C>A p.Pro429Gln	missense	Exon 13 of 16	Prot: NP_036354.1 UniProt:

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1295C>Ap.Pro432Gln

Exon rankExon 13 of 16

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1211C>Ap.Pro404Gln

Exon rankExon 13 of 16

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1286C>Ap.Pro429Gln

Exon rankExon 13 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.1295C>A p.Pro432Gln	missense	Exon 13 of 16	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000456914.7	TSL:1MANE Select	c.1211C>A p.Pro404Gln	missense	Exon 13 of 16	Prot: ENSP00000407590.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.1286C>A p.Pro429Gln	missense	Exon 13 of 16	Prot: ENSP00000361170.3 UniProt:

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1295C>Ap.Pro432Gln

Exon rankExon 13 of 16

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1211C>Ap.Pro404Gln

Exon rankExon 13 of 16

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1286C>Ap.Pro429Gln

Exon rankExon 13 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:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 2 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.78	D
FuncVEP CTI	Benign	0.075
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.60	T
Mutation Taster	N/A	48/52	disease causing
MutationAssessor	Uncertain	2.6	M
PhyloP100	Benign	0.83
popEVE	Benign	-3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.43
Sift	Benign	0.088	T
Sift4G	Uncertain	0.050	T
Varity_R	N/A	0.16
VESM-3B	Benign	-4.9

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

dbSNP: rs1276625381;

hg19: chr1-45797120;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar