1-45333448-C-T

Position:

• chr1-45333448-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000456914.7(MUTYH):​c.229G>A​(p.Asp77Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D77G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000456914.7
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.313G>A	p.Asp105Asn	missense_variant	3/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.229G>A	p.Asp77Asn	missense_variant	3/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.313G>A	p.Asp105Asn	missense_variant	3/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.229G>A	p.Asp77Asn	missense_variant	3/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251488 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461870 Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13 AN XY: 727242

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000889 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2022	Published functional studies demonstrate no damaging effect (Komine et al., 2015; Shinmura et al., 2016); Observed in individuals with a personal or family history of colorectal cancer and/or polyps (Nielsen et al., 2005; Niessen et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Asp91Asn); This variant is associated with the following publications: (PMID: 16408224, 16140997, 25820570, 26694661) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 02, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial adenomatous polyposis 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 09, 2024	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 105 of the MUTYH protein (p.Asp105Asn). This variant is present in population databases (rs587780746, gnomAD 0.007%). This missense change has been observed in individual(s) with sporadic colorectal cancer (PMID: 16140997, 16408224). This variant is also known as c.271G>A and p.Asp91Asn. ClinVar contains an entry for this variant (Variation ID: 135986). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26694661). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;.;.;T;.;.;.;T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.058	T;T;T;T;T;D;D;T;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.65, 0.93, 0.80	.;.;.;.;.;P;P;.;P;.;.;.
Vest4		0.65
MVP		0.94
MPC		0.13
ClinPred		0.81	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780746; hg19: chr1-45799120;