Genetic Variant NM_001128425.2:c.734G>A (chr1-45332445-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM1PM5PP3_ModeratePP5_Very_Strong

The NM_001128425.2(MUTYH):c.734G>A(p.Arg245His) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000183816: Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali, 2008" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R245L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30O:1

Conservation

PhyloP100: 7.14

Publications

64 publications found

Variant links:

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000183816: Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali, 2008; Komine, 2015).; SCV000537663: Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162).; SCV000821746: Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).; SCV000253868: Experimental studies have shown that this missense change affects MUTYH function (PMID: 17081686, 18534194, 23108399, 24569162, 25820570).; SCV000919794: Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).; SCV004839195: Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162).; SCV004848008: Functional studies provide some evidence that the p.Arg245His variant has impaired function in vitro (Ali 2008, Ruggieri 2013, Grasso 2014, Komine 2015).; SCV000601660: Experimental studies indicate the variant is damaging to MUTYH protein function (PMID: 24569162 (2014), 23108399 (2013), 18534194 (2008)).; SCV006325333: Functional studies indicate that this sequence change has a damaging effect on MUTYH function (PMID: 23108399, 18534194, 24569162, 25820570).; SCV000592696: Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014).; SCV004116023: Functional studies of the p.Arg245His variant demonstrate that it is deficient in enzymatic and DNA binding activities (Ali et al. 2008. PubMed ID: 18534194), and that it is associated with a statistically significant increase in spontaneous mutation frequency in both homozygous and monoallelic heterozygous lymphoblastoid cell lines derived from MUTYH-associated polyposis patients (Grasso et al. 2014. PubMed ID: 24569162).

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 35 uncertain in NM_001128425.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332445-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2733895.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 1-45332445-C-T is Pathogenic according to our data. Variant chr1-45332445-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 140877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUTYH	NM_001128425.2	MANE Plus Clinical	c.734G>A	p.Arg245His	missense	Exon 9 of 16	NP_001121897.1	E5KP25
MUTYH	NM_001048174.2	MANE Select	c.650G>A	p.Arg217His	missense	Exon 9 of 16	NP_001041639.1	Q9UIF7-6
MUTYH	NM_012222.3		c.725G>A	p.Arg242His	missense	Exon 9 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUTYH	ENST00000710952.2	MANE Plus Clinical	c.734G>A	p.Arg245His	missense	Exon 9 of 16	ENSP00000518552.2	E5KP25
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.650G>A	p.Arg217His	missense	Exon 9 of 16	ENSP00000407590.2	Q9UIF7-6
MUTYH	ENST00000372098.7	TSL:1	c.725G>A	p.Arg242His	missense	Exon 9 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000839

AC:

AN:

250298

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000647

AC:

AN:

1111980

Other (OTH)

AF:

0.0000994

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000577

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial adenomatous polyposis 2 (10)

not provided (9)

Hereditary cancer-predisposing syndrome (5)

Breast carcinoma (2)

Carcinoma of colon (1)

Diffuse midline glioma, H3 K27-altered (1)

Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

MUTYH-related disorder (1)

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PhyloP100

7.1

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.99

MPC

0.60

ClinPred

0.98

GERP RS

5.6

PromoterAI

-0.00060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.91

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over