rs587778542

chr1-45329409-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001048174.2(MUTYH):c.1463C>T(p.Pro488Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. P488Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4 O:1
• Conservation: PhyloP100: 1.23

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1603193).
• BP6: Variant 1-45329409-G-A is Benign according to our data. Variant chr1-45329409-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134867.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=2, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1547C>T	p.Pro516Leu	missense_variant	16/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1463C>T	p.Pro488Leu	missense_variant	16/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1547C>T	p.Pro516Leu	missense_variant	16/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1463C>T	p.Pro488Leu	missense_variant	16/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152134 Hom.: 0 Cov.: 31

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: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

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: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 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: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

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: 0.0000588

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 516 of the MUTYH protein (p.Pro516Leu). This variant is present in population databases (rs587778542, gnomAD 0.004%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 20618354). This variant is also known as p.P502L. ClinVar contains an entry for this variant (Variation ID: 134867). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26377631). 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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2019	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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2017	This variant is denoted MUTYH c.1547C>T at the cDNA level, p.Pro516Leu (P516L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant, previously reported as MYH 1505C>T (P502L) using an alternate reference sequence, has been observed in at least one individual with colon adenomas as well as in two healthy controls (Fleischmann 2004, Al-Tassan 2004, Morak 2010). In functional studies, this variant showed complementation of functional deficiency, DNA binding, and glycosylase activity similar to wild-type, but reduced binding to protein partner PCNA (Brinkmeyer 2015, Komine 2015). MUTYH Pro516Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro516Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MUTYH Pro516Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2021	Variant summary: MUTYH c.1547C>T (p.Pro516Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547C>T has been reported in the literature as a monoallelic variant in at-least one individual affected with APC-mutation negative attenuated familial adenomatous polyposis (AFAP stage III) who reported a negative family history (example, Morak_2010). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation (example, Brinkemeyer_2015, Komine_2015). Both these studies showed no damaging effect of this variant reporting similar DNA binding and glycosylase activity to wild-type enzyme (Brinkemeyer_2015) and a functionally retained ability to compliment the deficiency in an Mut Y disrupted E Coli system by monitoring spontaneous mutation rates (Komine_2015). However, a reduced affinity for PCNA (proliferation cell nuclear antigen), a binding partner of MUTYH protein, was also reported (Brinkmeyer_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of unequivocal clinical evidence and supportive functional evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Benign	0.86
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.071	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.036
Sift	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.018, 0.11, 0.017	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.10
MutPred		0.41		.;.;.;.;.;.;.;.;.;.;Loss of glycosylation at P516 (P = 0.0167);.;
MVP		0.82
MPC		0.12
ClinPred		0.11	T
GERP RS		2.6
Varity_R		0.034
gMVP		0.22

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: rs587778542; hg19: chr1-45795081;