rs587782773

Positions:

• chr1-45331772-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001048174.2(MUTYH):​c.991C>A​(p.Pro331Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,672 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P331L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 9.55

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1075C>A	p.Pro359Thr	missense_variant	12/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.991C>A	p.Pro331Thr	missense_variant	12/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1075C>A	p.Pro359Thr	missense_variant	12/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.991C>A	p.Pro331Thr	missense_variant	12/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248940 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134858

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: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461466 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727004

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: 0.0000405

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 24, 2023	The MUTYH c.1075C>A (p.Pro359Thr) missense change has a maximum subpopulation frequency of 0.0031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in one individual with colorectal cancer who also harbored the p.Tyr179Cys pathogenic variant, however phase for the variants was not determined (PMID: 28944238). This individual met the Amsterdam Criteria I for Lynch syndrome, but tumor profiling demonstrated normal mismatch repair function (microsatellite stable) and/or normal expression of four MMR proteins encoded by MLH1, MSH2, MSH6, and PMS2 in the tumor (PMID: 28944238). This variant is also known as c.1033C>A (p.P345T) in published literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 359 of the MUTYH protein (p.Pro359Thr). This variant is present in population databases (rs587782773, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-related disease (PMID: 17161978, 17581577, 28944238). This variant is also known as P345T. ClinVar contains an entry for this variant (Variation ID: 142860). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces proline with threonine at codon 359 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with colorectal cancer in conjunction with another MUTYH variant (PMID: 28944238). This variant has been identified in 4/280336 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. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2022	The MUTYH c.1075C>A; p.Pro359Thr variant (rs587782773), also known as P345T, is reported in the literature in individuals affected with MUTYH-associated polyposis (Cheadle 2007, DeRycke 2017, Morak 2010). At least two individuals had a second MUTYH variant, but phase was not determined (DeRycke 2017, Morak 2010). This variant is also reported in ClinVar (Variation ID: 142860) and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 359 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.857). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Cheadle JP and Sampson JR. MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. DNA Repair (Amst). 2007 Mar 1;6(3):274-9. PMID: 17161978. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. PMID: 28944238. Morak M et al. MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet. 2010 Oct;78(4):353-63. PMID: 20618354. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2020	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17161978, 28944238, 20618354, 17581577, 30719162, 27153395, 19725997) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2022	Variant summary: MUTYH c.1075C>A (p.Pro359Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248940 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1075C>A has been reported in the literature in individuals affected with MUTYH-Associated Polyposis (DeRycke_2017). This report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2023	This missense variant replaces proline with threonine at codon 359 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with colorectal cancer in conjunction with another MUTYH variant (PMID: 28944238). This variant has been identified in 4/280336 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	Ambry Genetics	Dec 08, 2023	The p.P359T variant (also known as c.1075C>A), located in coding exon 12 of the MUTYH gene, results from a C to A substitution at nucleotide position 1075. The proline at codon 359 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in the literature as an undefined rare variant that was identified in combination with another MUTYH mutation in a patient who had colorectal cancer diagnosed under the age of sixty with at least two affected family members; however, phase for the two variants (whether in cis or trans) was not determined (Cheadle JP and Sampson JR. DNA Repair (Amst.) 2007 Mar; 6(3):274-9). This alteration was also identified in an individual in conjunction with the p.Y179C MUTYH pathogenic variant; however, phase for the two variants was not determined. Furthermore, the individual in which these two MUTYH variants were identified met Amsterdam I criteria for Lynch syndrome, but had normal mismatch repair (MMR) function by tumor testing which demonstrated microsatellite stability and/or normal expression of the four MMR proteins (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Of note, this alteration is also designated as c.1033C>A (p.P345T) in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D;D;D;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	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
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.
Vest4		0.74
MVP		0.99
MPC		0.58
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587782773; hg19: chr1-45797444;