1-45332181-G-C

Position:

• chr1-45332181-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001048174.2(MUTYH):​c.834C>G​(p.Cys278Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C278F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 1.46

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 1-45332181-G-C is Pathogenic according to our data. Variant chr1-45332181-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182693.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.834C>G	p.Cys278Trp	missense_variant	10/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.834C>G	p.Cys278Trp	missense_variant	10/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1422C>G		non_coding_transcript_exon_variant	14/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This missense variant replaces cysteine with tryptophan at codon 306 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in markedly reduced glycosylase activity and decreased DNA binding compared to wild type MUTYH protein (PMID: 29915346, 31220976). This variant has been reported in trans with a pathogenic MUTYH co-variant, c.1187G>A (p.Gly396Asp), in an individual with colonic polyposis and significant family history of colon cancer (PMID 29915346). This variant has also been reported in an individual affected with breast cancer (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2022	The p.C306W pathogenic mutation (also known as c.918C>G), located in coding exon 10 of the MUTYH gene, results from a C to G substitution at nucleotide position 918. The cysteine at codon 306 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been identified in conjunction with pathogenic MUTYH founder mutations in probands with colonic polyposis and the variants were confirmed to be in trans in one of the cases (Ambry internal data, McDonnell KJ et al. Nat Chem, 2018 08;10:873-880). Furthermore, functional studies demonstrated severely reduced glycosylase activity and decreased DNA binding compared to wild type MUTYH, which was reported to be the result of reduced iron binding (McDonnell KJ et al. Nat Chem, 2018 08;10:873-880). Additionally, a study describing redox signaling interactions of DNA-processing [4Fe4S] enzymes found that this variant reduced DNA-bound redox activity, and was destabilizing, leading to rapid oxidative degradation of the [4Fe4S] cluster to the [3Fe-4S]+ species on a DNA electrode (Barton JK et al. Annu. Rev. Biochem., 2019 06;88:163-190). Based on internal structural analysis using a published crystal structure, this variant is anticipated to result in a significant decrease in structural stability and metal binding (Luncsford PJ et al. J. Mol. Biol., 2010 Oct;403:351-70). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial adenomatous polyposis 2 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 24, 2023	This missense variant replaces cysteine with tryptophan at codon 306 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in markedly reduced glycosylase activity and decreased DNA binding compared to wild type MUTYH protein (PMID: 29915346, 31220976). This variant has been reported in trans with a pathogenic MUTYH co-variant, c.1187G>A (p.Gly396Asp), in an individual with colonic polyposis and significant family history of colon cancer (PMID 29915346). This variant has also been reported in an individual affected with breast cancer (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 306 of the MUTYH protein (p.Cys306Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colon polyps (PMID: 29915346). ClinVar contains an entry for this variant (Variation ID: 182693). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 29915346). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 18, 2014

This variant is denoted MUTYH c.918C>G at the cDNA level, p.Cys306Trp (C306W) at the protein level, and results in the change of a Cysteine to a Tryptophan (TGC>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Cys306Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Cys306Trp occurs at a position that is conserved across species and is located in the FeS cluster region (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MUTYH Cys306Trp is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;.;.;.;.;D;.;.;.;T;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-9.3	D;D;D;D;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.98
MutPred		0.74		.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0221);.;.;.;
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881834; hg19: chr1-45797853;