rs760889663

chr1-45332195-C-Achr1-45332195-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001048174.2(MUTYH):c.820G>T(p.Val274Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. V274M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.26

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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18247429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.904G>T	p.Val302Leu	missense_variant	10/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.820G>T	p.Val274Leu	missense_variant	10/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.904G>T	p.Val302Leu	missense_variant	10/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.820G>T	p.Val274Leu	missense_variant	10/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251236 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.0000617

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461876 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 302 of the MUTYH protein (p.Val302Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with polyposis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 481791). 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. 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

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2022	The p.V302L variant (also known as c.904G>T), located in coding exon 10 of the MUTYH gene, results from a G to T substitution at nucleotide position 904. The valine at codon 302 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 15, 2019

Variant summary: MUTYH c.904G>T (p.Val302Leu) results in a 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 8.1e-06 in 246108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.904G>T in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 16, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25275298) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;.;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;.;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0080, 0.0050	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.28
MutPred		0.49		.;.;.;.;.;.;.;.;Loss of catalytic residue at V302 (P = 0.1267);.;.;.;
MVP		0.85
MPC		0.12
ClinPred		0.10	T
GERP RS		3.8
Varity_R		0.39
gMVP		0.67

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: rs760889663; hg19: chr1-45797867; COSMIC: COSV58343844; COSMIC: COSV58343844;