rs375349172

Positions:

• chr1-45334511-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128425.2(MUTYH):​c.37G>A​(p.Ala13Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A13V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense, splice_region
• Scores: Splicing: ADA: 0.001886
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: -0.364

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08023766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.-6G>A		splice_region_variant	2/16	ENST00000456914.7	NP_001041639.1
MUTYH	NM_001048174.2	c.-6G>A		5_prime_UTR_variant	2/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.-6G>A		splice_region_variant	2/16	1	NM_001048174.2	ENSP00000407590.2
MUTYH	ENST00000456914.7	c.-6G>A		5_prime_UTR_variant	2/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.541G>A		splice_region_variant, non_coding_transcript_exon_variant	6/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727194

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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	All of Us Research Program, National Institutes of Health	Apr 03, 2023	This missense variant replaces alanine with threonine at codon 13 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a heterozygous individual affected with polyposis (PMID; 21777424) and in a male individual affected with breast cancer (PMID: 30564557). This variant has not been identified 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	Dec 12, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the MUTYH protein (p.Ala13Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polyposis and/or breast cancer (PMID: 21777424, 30564557). ClinVar contains an entry for this variant (Variation ID: 216520). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 03, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces alanine with threonine at codon 13 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a heterozygous individual affected with polyposis (PMID; 21777424) and in a male individual affected with breast cancer (PMID: 30564557). This variant has not been identified 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	Mar 17, 2023	The p.A13T variant (also known as c.37G>A) is located in coding exon 2 of the MUTYH gene. The alanine at codon 13 is replaced by threonine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 2. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This alteration was reported in one individual from a cohort of 88 individuals with clinical features of Multiple Adenomatous Polyposis; no other MUTYH alterations were identified in this individual (Tricarico R et al. BMC Cancer, 2011 Jul;11:305). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ala13Thr variant was identified in the literature in 1 of 156 proband chromosomes from individuals with mixed CRC phenotypes and was not identified in 20 control chromosomes (Tricarico 2011); however, this limited set of cases and controls is not sufficient to be able to predict the significance of this variant. This variant was identified by the ESP in 1 of 8600 chromsomes (frequency of 0.0001); this limited number of observations is not sufficient to determine whether or not this is a low frequency common benign variant or a rare pathogenic variant. The p.Al13 residue is not present in all mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The p.Al13Thr (c.37G>A) variant occurs in the first base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, splicing in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a significant difference in splicing in 3 of 5 different programs. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer and/or polyps as well as male breast cancer (Tricario 2011, Rizzolo 2018); This variant is associated with the following publications: (PMID: 23599153, 30564557, 21777424) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;.;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.55	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.080	T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.90	L;L;L;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.041	D;T;T;D;T
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.
Vest4		0.17
MVP		0.43
MPC		0.12
ClinPred		0.11	T
GERP RS		-0.59
Varity_R		0.048
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.14
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: rs375349172; hg19: chr1-45800183;