1-45334506-G-C

Variant names:

• chr1-45334506-G-C
• rs202240122
• NM_001048174.2:c.-1C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001048174.2(MUTYH):​c.-1C>G variant causes a 5 prime UTR premature start codon gain 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 4 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32259232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.-1C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 16	ENST00000456914.7	NP_001041639.1
MUTYH	NM_001128425.2	c.42C>G	p.Ile14Met	missense_variant	Exon 2 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.-1C>G		5_prime_UTR_variant	Exon 2 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.-1C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 16	1	NM_001048174.2	ENSP00000407590.2
MUTYH	ENST00000710952.2	c.42C>G	p.Ile14Met	missense_variant	Exon 2 of 16		NM_001128425.2	ENSP00000518552.2
ENSG00000288208	ENST00000671898.1	n.546C>G		non_coding_transcript_exon_variant	Exon 6 of 21			ENSP00000499896.1
MUTYH	ENST00000456914.7	c.-1C>G		5_prime_UTR_variant	Exon 2 of 16	1	NM_001048174.2	ENSP00000407590.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 22, 2013

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I14M variant (also known as c.42C>G) is located in coding exon 2 of the MUTYH gene. This alteration results from a C to G substitution at nucleotide position 42. The isoleucine at codon 14 is replaced by methionine, an amino acid with highly similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 8600 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be benign but deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.I14M remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.094	T;.;.;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.3	L;L;L;.;.
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.060	N;N;N;N;N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.26	T;T;T;T;D
Vest4		0.39
ClinPred		0.90	D
GERP RS		3.4
Varity_R		0.23
gMVP		0.27
Mutation Taster		=90/10	polymorphism

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: rs202240122; hg19: chr1-45800178;