1-45332225-G-C

Variant names:

• chr1-45332225-G-C
• rs587781949
• NM_001128425.2:c.874C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001048174.2(MUTYH):​c.790C>G​(p.Pro264Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P264L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.74
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 49 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

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.874C>G	p.Pro292Ala	missense	Exon 10 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.790C>G	p.Pro264Ala	missense	Exon 10 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.865C>G	p.Pro289Ala	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.874C>G	p.Pro292Ala	missense	Exon 10 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.790C>G	p.Pro264Ala	missense	Exon 10 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.865C>G	p.Pro289Ala	missense	Exon 10 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	Familial adenomatous polyposis 2 (2)
-	1	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.027	D
Sift4G	Benign	0.063	T
Polyphen		0.94	P
Vest4		0.79
MutPred		0.49		Loss of sheet (P = 0.0817)
MVP		0.97
MPC		0.40
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.00040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.74
Mutation Taster		=8/92	disease causing

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: rs587781949; hg19: chr1-45797897;