NM_001128425.2:c.1437_1439delGGA

Variant names:

• chr1-45331218-TTCC-T
• rs587778541
• NM_001128425.2:c.1437_1439delGGA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM4_Supporting PP5_Very_Strong

The NM_001128425.2(MUTYH):​c.1437_1439delGGA​(p.Glu480del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000184946: Functional analysis of this alteration has demonstrated lack of DNA binding capacity and DNA glycosylase activity and an association with defective DNA damage repair following oxidative stress, supporting a pathogenic role in polyp development (Molatore S et al. Hum. Mutat. 2010 Feb;31:159-66; D'Agostino VG et al. DNA Repair (Amst). 2010 Jun;9:700-7; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11).; SCV000685578: Experimental studies of MUTYH protein function have shown this variant to be deficient in DNA glycosylase activity and display reduced binding affinity for and repair kinetics toward 8-oxoG (PMID:19953527, 20418187, 20848659, 23108399, 25820570).; SCV000821745: Multiple in vivo and in vitro functional studies have demonstrated that this variant results in the defective function of the MUTYH protein (PMID:19953527, PMID:23108399, PMID:20848659).; SCV000166448: Experimental studies have shown that this variant affects MUTYH function (PMID:20418187, 20848659, 23108399).; SCV000271402: In vitro functional studies provide some evidence that the p.Glu480del variant may impact protein function (Dagostino 2010, Goto 2010, Molatore 2010).; SCV000357889: In vitro testing demonstrated that the p.Glu466del variant was dysfunctional in base excision repair and had severely impaired enzymatic activity (Molatore et al. 2010; D'Agostino et al. 2010; Komine et al. 2015).; SCV000592718: "In vitro analysis identified severe reduction in the variant protein’s binding affinity towards an 8-oxoG:A DNA substrate as compared to the wild-type protein; this reduced binding was always associated with impairment of glycosylase activity, with adenine removal being totally abrogated." (Dagostino 2010, Gismondi 2004, Malatore 2009); SCV000917798: Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples- Goto_2010, Komine_2015).; SCV004015246: Experimental studies have shown that this in-frame deletion disrupts MUTYH protein function (PMID:23108399, 20848659, 20418187).; SCV004829751: Experimental studies have shown that this variant causes impaired MUTYH protein function (PMID:19953527, 20418187, 20848659, 23108399, 25820570).; SCV000149667: Published functional studies demonstrate a damaging effect: defective base excision repair (Molatore 2010, D'Agostino 2010, Goto 2010, Ruggieri 2013); SCV000601634: Functional evidence suggests that this variant may impact protein function (PMIDs:25820570 (2015), 20848659 (2010)).". Synonymous variant affecting the same amino acid position (i.e. E479E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: MUTYH NM_001128425.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34 O:2
• Conservation: PhyloP100: 7.31
• Publications: 42 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: 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

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000184946: Functional analysis of this alteration has demonstrated lack of DNA binding capacity and DNA glycosylase activity and an association with defective DNA damage repair following oxidative stress, supporting a pathogenic role in polyp development (Molatore S et al. Hum. Mutat. 2010 Feb;31:159-66; D'Agostino VG et al. DNA Repair (Amst). 2010 Jun;9:700-7; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11).; SCV000685578: Experimental studies of MUTYH protein function have shown this variant to be deficient in DNA glycosylase activity and display reduced binding affinity for and repair kinetics toward 8-oxoG (PMID: 19953527, 20418187, 20848659, 23108399, 25820570).; SCV000821745: Multiple in vivo and in vitro functional studies have demonstrated that this variant results in the defective function of the MUTYH protein (PMID: 19953527, PMID: 23108399, PMID: 20848659).; SCV000166448: Experimental studies have shown that this variant affects MUTYH function (PMID: 20418187, 20848659, 23108399).; SCV000271402: In vitro functional studies provide some evidence that the p.Glu480del variant may impact protein function (Dagostino 2010, Goto 2010, Molatore 2010).; SCV000357889: In vitro testing demonstrated that the p.Glu466del variant was dysfunctional in base excision repair and had severely impaired enzymatic activity (Molatore et al. 2010; D'Agostino et al. 2010; Komine et al. 2015).; SCV000592718: "In vitro analysis identified severe reduction in the variant protein’s binding affinity towards an 8-oxoG:A DNA substrate as compared to the wild-type protein; this reduced binding was always associated with impairment of glycosylase activity, with adenine removal being totally abrogated." (Dagostino 2010, Gismondi 2004, Malatore 2009); SCV000917798: Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples- Goto_2010, Komine_2015).; SCV004015246: Experimental studies have shown that this in-frame deletion disrupts MUTYH protein function (PMID: 23108399, 20848659, 20418187).; SCV004829751: Experimental studies have shown that this variant causes impaired MUTYH protein function (PMID: 19953527, 20418187, 20848659, 23108399, 25820570).; SCV000149667: Published functional studies demonstrate a damaging effect: defective base excision repair (Molatore 2010, D'Agostino 2010, Goto 2010, Ruggieri 2013); SCV000601634: Functional evidence suggests that this variant may impact protein function (PMIDs:25820570 (2015), 20848659 (2010)).
• PM4: Nonframeshift variant in NON repetitive region in NM_001128425.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-45331218-TTCC-T is Pathogenic according to our data. Variant chr1-45331218-TTCC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127838.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1437_1439delGGA	p.Glu480del	disruptive_inframe_deletion	Exon 14 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1353_1355delGGA	p.Glu452del	disruptive_inframe_deletion	Exon 14 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1428_1430delGGA	p.Glu477del	disruptive_inframe_deletion	Exon 14 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1437_1439delGGA	p.Glu480del	disruptive_inframe_deletion	Exon 14 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1353_1355delGGA	p.Glu452del	disruptive_inframe_deletion	Exon 14 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1428_1430delGGA	p.Glu477del	disruptive_inframe_deletion	Exon 14 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000954 AC: 24 AN: 251478 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461892 Hom.: 1 AF XY: 0.0000591 AC XY: 43 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68010

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Familial adenomatous polyposis 2 (16)
10	-	-	not provided (10)
5	-	-	Hereditary cancer-predisposing syndrome (5)
1	-	-	Breast carcinoma (1)
1	-	-	Colorectal polyposis (1)
1	-	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587778541; hg19: chr1-45796890;