rs374950566

Variant names:

• chr1-45332215-G-A
• rs374950566
• NM_001128425.2:c.884C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PP3_Strong PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.800C>T​(p.Pro267Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000215289: "In vitro functional studies demonstrate DNA binding activity and base excision repair activity are severely defective (Ali M et al. Gastroenterology 2008 Aug; 135(2):499-507; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11)."; SCV000685679: Functional studies have shown that this variant has a deleterious impact on mismatch repair and DNA-binding (PMID:18534194, 26377631).; SCV000821747: Experimental studies have confirmed the disrupting effect of this variant in the protein function (PMID:25820570, PMID:26377631).; SCV000293494: Published functional studies demonstrate a damaging effect: defective DNA binding capability, compromised base excision activity, and near absent glycosylase activity (Ali et al., 2008; Brinkmeyer et al., 2015; Komine et al., 2015); SCV001248081: PS3:Moderate; SCV005622987: Functional studies showed this variant had severely defective DNA binding and defective glycosylase activity (PMIDs: 18534194 (2008), 26377631 (2015)). It was also unable to suppress spontaneous mutations compared to the wild-type (PMID:25820570 (2015)).; SCV000545714: Experimental studies have shown that this missense change affects MUTYH function (PMID:18534194, 25820570, 26377631).; SCV004841020: Functional studies have shown that this variant causes deficient mismatch repair and DNA-binding (PMID:18534194, 26377631).; SCV006073854: Several publications report experimental evidence evaluating an impact on protein function and have found that the variant has severely defective glycosylase activity as well as DNA binding activity (e.g. Ali_2008, Komine_2015, Brinkmeyer_2015). PMID:18534194, 35734982, 26377631, 25820570, 19732775; SCV000592700: an in vitro functional study demonstrated that the p.Pro295Leu variant was severely defective in both glycosylase and DNA binding (Ali 2008).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P267S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 7.74
• Publications: 29 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000215289: "In vitro functional studies demonstrate DNA binding activity and base excision repair activity are severely defective (Ali M et al. Gastroenterology 2008 Aug; 135(2):499-507; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11)."; SCV000685679: Functional studies have shown that this variant has a deleterious impact on mismatch repair and DNA-binding (PMID: 18534194, 26377631).; SCV000821747: Experimental studies have confirmed the disrupting effect of this variant in the protein function (PMID: 25820570, PMID: 26377631).; SCV000293494: Published functional studies demonstrate a damaging effect: defective DNA binding capability, compromised base excision activity, and near absent glycosylase activity (Ali et al., 2008; Brinkmeyer et al., 2015; Komine et al., 2015); SCV001248081: PS3:Moderate; SCV005622987: Functional studies showed this variant had severely defective DNA binding and defective glycosylase activity (PMIDs: 18534194 (2008), 26377631 (2015)). It was also unable to suppress spontaneous mutations compared to the wild-type (PMID: 25820570 (2015)).; SCV000545714: Experimental studies have shown that this missense change affects MUTYH function (PMID: 18534194, 25820570, 26377631).; SCV004841020: Functional studies have shown that this variant causes deficient mismatch repair and DNA-binding (PMID: 18534194, 26377631).; SCV006073854: Several publications report experimental evidence evaluating an impact on protein function and have found that the variant has severely defective glycosylase activity as well as DNA binding activity (e.g. Ali_2008, Komine_2015, Brinkmeyer_2015). PMID: 18534194, 35734982, 26377631, 25820570, 19732775; SCV000592700: an in vitro functional study demonstrated that the p.Pro295Leu variant was severely defective in both glycosylase and DNA binding (Ali 2008).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 56 uncertain in NM_001048174.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-45332215-G-A is Pathogenic according to our data. Variant chr1-45332215-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 185242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048174.2. 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.884C>T	p.Pro295Leu	missense	Exon 10 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.800C>T	p.Pro267Leu	missense	Exon 10 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.875C>T	p.Pro292Leu	missense	Exon 10 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.884C>T	p.Pro295Leu	missense	Exon 10 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.800C>T	p.Pro267Leu	missense	Exon 10 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.875C>T	p.Pro292Leu	missense	Exon 10 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251116 AF XY: 0.0000147

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461848 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 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: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111982

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Familial adenomatous polyposis 2 (10)
10	-	-	not provided (10)
4	-	-	Hereditary cancer-predisposing syndrome (4)
1	-	-	Breast carcinoma (1)
1	-	-	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs374950566; hg19: chr1-45797887;