NM_001048174.2:c.1069G>A

Variant names:

• chr1-45331694-C-T
• rs876659232
• NM_001048174.2:c.1069G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.1069G>A​(p.Ala357Thr) 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. 16/22 in silico tools predict a benign outcome for this variant. 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. A357P) 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: 1.93
• Publications: 3 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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 47 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13359901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1069G>A	p.Ala357Thr	missense_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1069G>A	p.Ala357Thr	missense_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1657G>A		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

May 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 385 of the MUTYH protein (p.Ala385Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database in an individual affected with breast cancer co-occurring with another rare missense change (PMID: 21520333). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	.;.;.;.;.;T;.;.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	.;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.23	.;.;.;.;.;N;.;.;.;.
PhyloP100		1.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.33	N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0040, 0.0020	.;.;.;.;.;B;B;.;B;.
Vest4		0.052
MutPred		0.41		.;.;.;.;.;.;.;.;Loss of stability (P = 0.1463);.;
MVP		0.93
MPC		0.11
ClinPred		0.19	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.31
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876659232; hg19: chr1-45797366;