rs1060501325

Variant names:

• chr1-45331462-C-A
• rs1060501325
• NM_001128425.2:c.1281G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45331462-C-A
• chr1-45331462-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_001128425.2(MUTYH):​c.1281G>T​(p.Trp427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. W427L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.12
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 60 uncertain in NM_001128425.2
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-45331462-C-A is Benign according to our data. Variant chr1-45331462-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2061307.

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.1281G>T	p.Trp427Cys	missense	Exon 13 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1197G>T	p.Trp399Cys	missense	Exon 13 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1272G>T	p.Trp424Cys	missense	Exon 13 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.1281G>T	p.Trp427Cys	missense	Exon 13 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1197G>T	p.Trp399Cys	missense	Exon 13 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1272G>T	p.Trp424Cys	missense	Exon 13 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 2 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.048	D
Polyphen		0.023	B
Vest4		0.45
MutPred		0.70		Loss of catalytic residue at P430 (P = 0.0327)
MVP		0.97
MPC		0.66
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.67
Mutation Taster		=43/57	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: rs1060501325; hg19: chr1-45797134;