rs1057517765

Positions:

• chr1-45332466-T-C
• chr1-45332466-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001048174.2(MUTYH):​c.629A>G​(p.Asn210Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,788 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. N210T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 5.75

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-45332466-T-C is Pathogenic according to our data. Variant chr1-45332466-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372416.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}. Variant chr1-45332466-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.713A>G	p.Asn238Ser	missense_variant	9/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.629A>G	p.Asn210Ser	missense_variant	9/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.713A>G	p.Asn238Ser	missense_variant	9/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.629A>G	p.Asn210Ser	missense_variant	9/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461788 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	Variant summary: MUTYH c.713A>G (p.Asn238Ser) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. This variant is also reported in the literature as c.671A>G (p.Asn224Ser) and c.704A>G (p.Asn235Ser) using alternate transcripts. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250588 control chromosomes (gnomAD). c.713A>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Dallosso_2008, Jones_2009, Out_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal DNA glycosylase activity (Shinmura_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 238 of the MUTYH protein (p.Asn238Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and/or multiple colorectal adenomas (PMID: 18515411). This variant is also known as c.704A>G (N235S). ClinVar contains an entry for this variant (Variation ID: 372416). 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: 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 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This missense variant replaces asparagine with serine at codon 238 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). A functional study has shown that this variant causes severe defect in the DNA glycosylase activity of MUTYH protein and ability to suppress mutations caused by 8-hydroxyguanine (PMID: 26694661). This variant has been reported in two individuals affected with polyposis and colorectal cancer in compound heterozygous state with a known pathogenic variant (PMID: 18515411, 19732775) and in one individual with pancreatic cancer (PMID: 34659905). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2023	The p.N238S variant (also known as c.713A>G), located in coding exon 9 of the MUTYH gene, results from an A to G substitution at nucleotide position 713. The asparagine at codon 238 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state in individuals with polyps as well as colorectal cancer and in an individual with adenomatous polyposis (Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10; Dallosso AR et al. Gut 2008 Sep;57(9):1252-5; Ambry internal data). It was also reported in a patient with features of MUTYH associated polyposis, but no co-occurring MUTYH variant was reported (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). In addition, a functional assay demonstrated severely reduced (~2%) DNA glycosylase activity in a DNA cleavage activity assay using an A:8OHG substrate (Shinmura K et al. Hum. Mutat. 2016 Apr;37(4):350-3). Based on an internal structural analysis, this variant is more destabilizing to the MUTYH active site than other nearby pathogenic variants (Ambry internal data; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Woods RD et al. Nucleic Acids Res, 2016 Jan;44:801-10; Russelburg LP et al. ACS Chem Biol, 2020 01;15:93-102). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Carcinoma of colon Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Asn238Ser variant has been reported in the literature in 1/552 proband chromosomes in an individual with MAP and biallelic MUTYH mutations, although no control chromosomes were tested to establish its frequency in the general population (Vogt 2009). The patient from this study also harbored the MUTYH p.Gly396Asp variant, which has been previously reported as pathogenic (Kundu 2009). The p.Asn238 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Asn238Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. MUTYH-associated polyposis (MAP) is inherited in an autosomal recessive manner and two pathogenic variants, one on each chromosome are expected to cause the disorder. The presence of this variant in combination with a reported pathogenic variant increases the likelihood that the p.Asn238Ser variant is pathogenic. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2017

This variant is denoted MUTYH c.713A>G at the cDNA level, p.Asn238Ser (N238S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant, also published as Asn210Ser and Asn235Ser using alternate transcripts, has been observed at least once in the compound heterozygous state with a MUTYH founder pathogenic variant in an individual with early-onset colorectal cancer and multiple polyps (Dallosso 2008, Jones 2009). Shinmura et al. (2016) found this variant to cause severely defective DNA glycosylase activity and inability to suppress mutations induced by 8-hydroxyguanine. MUTYH Asn238Ser was not observed in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MUTYH Asn238Ser 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, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96, 1.0, 0.96	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.92
MutPred		0.96		.;.;.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;.;.;
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1057517765; hg19: chr1-45798138;