chr1-45331529-G-A

Variant names:

• chr1-45331529-G-A
• rs529008617
• NM_001128425.2:c.1214C>T
• MUTYH p.Pro405Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1_SupportingPM2_SupportingPM5PP3_StrongPP5_Strong

The NM_001048174.2(MUTYH):c.1130C>T (p.Pro377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000682 (AC=110) in the gnomAD database across 1,614,020 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000745. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186969: Functional analysis of this alteration has revealed compromised adenine glycosylase activity that was 30-40% of the activity of the wildtype enzyme (Kundu S et al. DNA Repair (Amst.) 2009 Dec;8:1400-10)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P377R: Likely_pathogenic (ClinVar VariationId 3914955, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P377= (synonymous): Likely_benign (ClinVar VariationId 232703, 2 stars); p.P377= (synonymous): Likely_benign (ClinVar VariationId 2065560, 2 stars); p.P377= (synonymous): Benign/Likely_benign (ClinVar VariationId 414158, 2 stars); p.P377S: Uncertain_significance (ClinVar VariationId 5298, 1 star); p.P377dup: Uncertain_significance (ClinVar VariationId 464679, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 O:2
• Conservation: PhyloP100: 7.17
• Publications: 34 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: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000186969: Functional analysis of this alteration has revealed compromised adenine glycosylase activity that was 30-40% of the activity of the wildtype enzyme (Kundu S et al. DNA Repair (Amst.) 2009 Dec;8:1400-10).; SCV000685555: Functional studies showed severely reduced glycosylase and bacterial complementation activities (PMID: 19836313, 20848659, 25820570).; SCV000592712: "functional studies analyzing the adenine glycosylase activity have shown that the variant showed compromised enzymatic activity that was 30–40% of the wild type enzyme." (Goto 2010, Kundu 2009); SCV000285918: Experimental studies have shown that this missense change affects MUTYH function (PMID: 19836313, 20848659, 23322991, 25820570).; SCV000915415: Functional studies demonstrated the variant resulted in severely impaired glycosylase activity (Kundu et al. 2009; Goto et al. 2010) and mutation suppression compared to wild type (Kundu et al. 2009; Shinmura et al. 2012; Komine et al. 2015).; SCV002500746: At least one publication reports experimental evidence evaluating an impact on protein function (Komine_2009). The most pronounced variant effect results in a functionally defective Base Excision Repair (BER) activity in a MutY-Deficient E. coli Complementation Assay.; SCV004838258: Functional studies showed severely reduced glycosylase and bacterial complementation activities (PMID: 19836313, 20848659, 25820570).; SCV004848061: In vitro functional studies provide some evidence that the p.Pro405Leu variant may impact protein function (Kundu 2009, Goto 2010, Shinmura 2012, Komine 2015).; SCV000490629: Published functional studies demonstrate a damaging effect: variant associated with severely impaired glycosylase activity and severely suppressed oxidative mutagenesis (Kundu et al., 2009; Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015)
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 11 benign (OR vs. background: 2.4).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000745 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00473) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.P377R: Likely_pathogenic (ClinVar VariationId 3914955, 1 star); Other variants at the same amino acid residue (not pathogenic): p.P377= (synonymous): Likely_benign (ClinVar VariationId 232703, 2 stars); p.P377= (synonymous): Likely_benign (ClinVar VariationId 2065560, 2 stars); p.P377= (synonymous): Benign/Likely_benign (ClinVar VariationId 414158, 2 stars); p.P377S: Uncertain_significance (ClinVar VariationId 5298, 1 star); p.P377dup: Uncertain_significance (ClinVar VariationId 464679, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (26/26 total P/LP).

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.1214C>T p.Pro405Leu	missense	Exon 13 of 16	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001048174.2	MANE Select	c.1130C>T p.Pro377Leu	missense	Exon 13 of 16	Prot: NP_001041639.1 UniProt:
	MUTYH NM_012222.3		c.1205C>T p.Pro402Leu	missense	Exon 13 of 16	Prot: NP_036354.1 UniProt:

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1214C>Tp.Pro405Leu

Exon rankExon 13 of 16

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1130C>Tp.Pro377Leu

Exon rankExon 13 of 16

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1205C>Tp.Pro402Leu

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.1214C>T p.Pro405Leu	missense	Exon 13 of 16	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000456914.7	TSL:1MANE Select	c.1130C>T p.Pro377Leu	missense	Exon 13 of 16	Prot: ENSP00000407590.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.1205C>T p.Pro402Leu	missense	Exon 13 of 16	Prot: ENSP00000361170.3 UniProt:

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1214C>Tp.Pro405Leu

Exon rankExon 13 of 16

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1130C>Tp.Pro377Leu

Exon rankExon 13 of 16

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1205C>Tp.Pro402Leu

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000394	AC:6	Hom:0	AN:152188	Cov:33
GnomAD2 exomes	AF: 0.0000719	AC:18	Hom:	AN:250510	Cov:
GnomAD4 exome	AF: 0.0000711	AC:104	Hom:0	AN:1461714	Cov:32
GnomAD4 genome	AF: 0.0000394	AC:6	Hom:0	AN:152306	Cov:33
TOPMed (Bravo)	AF: 0.0000264	AC:7	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000716	AC:18	Hom:0	AN:251322	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000180 *	2	11112	0.000114 *	2	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000246	7	28420	0.000139	4	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000598	4	66888
SCHEMA(Schizophrenia)	0.0000560	6	107228	0.0000886	14	157954

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Familial adenomatous polyposis 2 (13)
9	-	-	not provided (9)
2	-	-	Carcinoma of colon (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	B lymphoblastic leukemia lymphoma, no ICD-O subtype (1)
1	-	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-7.4
GPN-Star score	N/A	7.4
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.34	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.8	H
PhyloP100	Uncertain	7.2
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.1	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.80
VESM-3B	Benign	-12

Showing 30 of 30 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: rs529008617;

hg19: chr1-45797201;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar