rs267598622

Variant names:

• chr1-45331751-G-A
• rs267598622
• NM_001048174.2:c.1012C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45331751-G-A
• chr1-45331751-G-C
• chr1-45331751-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001048174.2(MUTYH):​c.1012C>T​(p.Pro338Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P338L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.11
• Publications: 1 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13845584).
• BP6: Variant 1-45331751-G-A is Benign according to our data. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819. Variant chr1-45331751-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 73819.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1012C>T	p.Pro338Ser	missense_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1012C>T	p.Pro338Ser	missense_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1600C>T		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250148 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461740 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with serine at codon 366 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 an individual affected with endometrial carcinoma (PMID: 27443514). This variant has been identified in 2/250148 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. -

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 366 of the MUTYH protein (p.Pro366Ser). This variant is present in population databases (rs267598622, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 73819). 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:1

May 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P366S variant (also known as c.1096C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1096. The proline at codon 366 is replaced by serine, an amino acid with similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This amino acid position is not well conserved in available 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.078	.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	.;.;.;.;.;L;.;.;.;.;.
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.056	T;T;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0040, 0.0060	.;.;.;.;.;B;B;.;B;.;.
Vest4		0.18
MutPred		0.33		.;.;.;.;.;.;.;.;Gain of phosphorylation at P366 (P = 0.0022);.;.;
MVP		0.91
MPC		0.12
ClinPred		0.099	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.40
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs267598622; hg19: chr1-45797423;