1-45332035-C-T

Variant names:

• chr1-45332035-C-T
• rs147718169
• NM_001048174.2:c.901G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001048174.2(MUTYH):​c.901G>A​(p.Val301Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. V301L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:2 O:1
• Conservation: PhyloP100: 0.0350

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02464962).
• BP6: Variant 1-45332035-C-T is Benign according to our data. Variant chr1-45332035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134859.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=14, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.901G>A	p.Val301Met	missense_variant	Exon 11 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.901G>A	p.Val301Met	missense_variant	Exon 11 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1489G>A		non_coding_transcript_exon_variant	Exon 15 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251434 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135910

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461888 Hom.: 1 Cov.: 36 AF XY: 0.000109 AC XY: 79 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74496

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:5 Benign:1

Sep 27, 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 valine with methionine at codon 329 of the MUTYH protein. This variant is also known as c.943G>A (p.Val315Pro) based on an alternative transcript (NM_001048171). 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 individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, and breast cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). This variant has also been identified in 23/282826 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 29, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Variant of Uncertain Significance was detected in MUTYH gene. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 329 of the MUTYH protein (p.Val329Met). This variant is present in population databases (rs147718169, gnomAD 0.01%). This variant has been reported in individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, and breast cancer cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). ClinVar contains an entry for this variant (Variation ID: 134859). Computational prediction suggests that this variant impact conflicting (SIFT: "Deleterious"; PolyPhen-2: "Benign"). 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. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:4

Dec 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with colon cancer and/or polyps and other cancers (PMID: 17207658, 25980754, 25186627, 27498913, 27829682, 29684080, 31062380); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.Val315Met and p.Val326Met; This variant is associated with the following publications: (PMID: 19300419, 17207658, 27829682, 27498913, 20571908, 25980754, 24728327, 16879101, 25186627, 29684080, 31062380, 33471991, 37013556, 36243179, 34326862, 35980532, 20816984, 35264596, 37306523, 26580448, 32923874, 37795462, 39541563) -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with suspected MUTYH-associated polyposis (PMID: 2829682 (2016)), Lynch syndrome-associated cancer or polyps (PMID: 25980754 (2015)), breast cancer (PMID: 35264596 (2022)), thyroid cancer (PMID: 29684080 (2018)), and squamous cell carcinoma (PMID: 17207658 (2007)). The frequency of this variant in the general population, 0.00011 (4/35436 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Val329Met variant was identified in 4 of 3176 proband chromosomes (frequency: 0.0013) in one individual with squamous cell carcinoma of the head and neck (Gorgens 2007), two individuals with MUTYH-associated polyposis (Ricci 2017) and one individual with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147718169) as “With Uncertain significance, other allele”, ClinVar (uncertain significance by Ambry Genetics, Invitae, GeneDx, Children's Hospital of Philadelphia, Counsyl, Fulgent Genetics, and Color), Clinvitae (4x), and Insight Colon Cancer Gene Variant Database. The variant was not identified in Cosmic, MutDB, or UMD-LSDB databases. The variant was also identified by our laboratory in 1 individual with Lynch Syndrome. The variant was identified in control databases in 23 of 277164 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24018 chromosomes (freq: 0.00008), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 5 of 34420 chromosomes (freq: 0.0001), European (Non-Finnish) in 12 of 126662 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Val329 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 uncertain significance. -

not specified Uncertain:3 Other:1

Jul 27, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 20, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.985G>A (p.Val329Met) 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 8.7e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (8.7e-05 vs 0.0046), allowing no conclusion about variant significance. c.985G>A variant has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Yurgelun_2015, Ricci_2016) and Rectal Colon cancer (AlHarbi_2023). This variant was also reported in the control cohort of a large case-control study of Biliary tract cancer (Okawa_2023). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 37306523, 24728327, 17207658, 36243179, 27829682, 19300419, 20571908, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 134859). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jul 07, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 15, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 19, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 329 of the MUTYH protein. This variant is also known as c.943G>A (p.Val315Pro) based on an alternative transcript (NM_001048171). 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 individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, or breast cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). This variant has also been identified in 23/282826 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. -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.071	.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.025	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.062
Sift	Uncertain	0.0050	D;D;D;D;D;T;D;D;D;.;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.75, 0.071, 0.077	.;.;.;.;.;P;B;.;B;.;.
Vest4		0.38
MVP		0.36
MPC		0.15
ClinPred		0.19	T
GERP RS		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.48

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: rs147718169; hg19: chr1-45797707;