1-45332576-G-C

Variant names:

• chr1-45332576-G-C
• rs1064796630
• NM_001128425.2:c.688C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_001048174.2(MUTYH):​c.604C>G​(p.Gln202Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q202R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense, splice_region
• Scores: Splicing: ADA: 0.1967
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.65
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 36 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332575-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 964790.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35185644).

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.688C>G	p.Gln230Glu	missense splice_region	Exon 8 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.604C>G	p.Gln202Glu	missense splice_region	Exon 8 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.679C>G	p.Gln227Glu	missense splice_region	Exon 8 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.688C>G	p.Gln230Glu	missense splice_region	Exon 8 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.604C>G	p.Gln202Glu	missense splice_region	Exon 8 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.679C>G	p.Gln227Glu	missense splice_region	Exon 8 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial adenomatous polyposis 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.073
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.29	N
PhyloP100		7.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.41
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.42
MutPred		0.57		Loss of MoRF binding (P = 0.1264)
MVP		0.88
MPC		0.13
ClinPred		0.74	D
GERP RS		5.4
PromoterAI		0.069	Neutral
Varity_R		0.27
gMVP		0.69
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.36
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

Other links and lift over

dbSNP: rs1064796630; hg19: chr1-45798248;