1-45331773-G-C

Variant names:

• chr1-45331773-G-C
• rs863224381
• NM_001128425.2:c.1074C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.990C>G​(p.Phe330Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. F330V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.479
• 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: 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17123783).

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.1074C>G	p.Phe358Leu	missense	Exon 12 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.990C>G	p.Phe330Leu	missense	Exon 12 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1065C>G	p.Phe355Leu	missense	Exon 12 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.1074C>G	p.Phe358Leu	missense	Exon 12 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.990C>G	p.Phe330Leu	missense	Exon 12 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1065C>G	p.Phe355Leu	missense	Exon 12 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		0.48
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.13
Sift	Benign	0.045	D
Sift4G	Benign	0.084	T
Polyphen		0.0010	B
Vest4		0.38
MutPred		0.37		Loss of sheet (P = 0.0126)
MVP		0.37
MPC		0.17
ClinPred		0.90	D
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.73
Mutation Taster		=31/69	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: rs863224381; hg19: chr1-45797445;