Genetic Variant NM_001128425.2:c.821G>A (chr1-45332278-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3PM1PM5PP5

The NM_001128425.2(MUTYH):c.821G>A(p.Arg274Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001134486: Functional studies indicate this variant causes significantly reduced glycosylase activity that was 15-21% of the wild-type, with neutral/moderate effect on DNA binding (PMIDs: 18534194 (2008), 19443904 (2009))." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:12O:1

Conservation

PhyloP100: 3.88

Publications

34 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: Likely_pathogenic. The variant received 9 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001134486: Functional studies indicate this variant causes significantly reduced glycosylase activity that was 15-21% of the wild-type, with neutral/moderate effect on DNA binding (PMIDs: 18534194 (2008), 19443904 (2009)).; SCV005875772: "In vitro functional analyses demonstrate reduced glycosylase activity, but conflicting results of DNA binding activity compared to wild type (Ali 2008, Forsbring 2009)."; SCV006325334: Functional studies indicate that this sequence change results in a reduction in glycosylase activity, however, these studies have shown conflicting results about the effect of this variant on DNA binding (PMID: 18534194, 19443904).; SCV000166460: Experimental studies have shown that this missense change affects MUTYH function (PMID: 18534194, 19443904).; SCV005689155: "in vitro analyses have demonstrated reduced functional activities compared to wild type MUTYH (PMID: 18534194, 19443904)."; SCV000183970: "In vitro analyses have demonstrated significantly reduced DNA glycosylase and DNA binding activities compared to wild type MUTYH (Ali M et al. Gastroenterology. 2008 Aug;135:499-507; Forsbring M et al. Carcinogenesis. 2009 Jul;30:1147-54)."

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 38 uncertain in NM_001128425.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332279-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-45332278-C-T is Pathogenic according to our data. Variant chr1-45332278-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41764.

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.821G>A	p.Arg274Gln	missense	Exon 10 of 16	NP_001121897.1	E5KP25
MUTYH	NM_001048174.2	MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 10 of 16	NP_001041639.1	Q9UIF7-6
MUTYH	NM_012222.3		c.812G>A	p.Arg271Gln	missense	Exon 10 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.821G>A	p.Arg274Gln	missense	Exon 10 of 16	ENSP00000518552.2	E5KP25
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 10 of 16	ENSP00000407590.2	Q9UIF7-6
MUTYH	ENST00000372098.7	TSL:1	c.812G>A	p.Arg271Gln	missense	Exon 10 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000172

AC:

AN:

250036

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000346

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000335

AC:

489

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000334

AC XY:

243

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000412

AC:

458

AN:

1111980

Other (OTH)

AF:

0.000431

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000210

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000371

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Familial adenomatous polyposis 2 (7)

Hereditary cancer-predisposing syndrome (4)

not specified (2)

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

MUTYH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.69

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.6

PhyloP100

3.9

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.83

Sift

Benign

0.049

Sift4G

Uncertain

0.017

Polyphen

0.99

Vest4

0.47

MVP

0.98

MPC

0.36

ClinPred

0.52

GERP RS

5.6

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.65

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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