rs768222428

Variant names:

• chr1-45331196-T-A
• rs768222428
• NM_001128425.2:c.1462A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45331196-T-A
• chr1-45331196-T-C
• chr1-45331196-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001128425.2(MUTYH):​c.1462A>T​(p.Thr488Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T488A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 0 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, 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: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1462A>T	p.Thr488Ser	missense	Exon 14 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1378A>T	p.Thr460Ser	missense	Exon 14 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1453A>T	p.Thr485Ser	missense	Exon 14 of 16	NP_036354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1462A>T	p.Thr488Ser	missense	Exon 14 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1378A>T	p.Thr460Ser	missense	Exon 14 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1453A>T	p.Thr485Ser	missense	Exon 14 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.66
MutPred		0.33		Gain of disorder (P = 0.0994)
MVP		0.94
MPC		0.15
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.34
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs768222428; hg19: chr1-45796868;