NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000467236.13

Allele description [Variation Report for NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr)]

NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr)

HGVS:

NC_000001.11:g.45334504A>G
NG_008189.1:g.10967T>C
NM_001048171.2:c.2T>C
NM_001048172.2:c.2T>C
NM_001048173.2:c.2T>C
NM_001048174.2:c.2T>CMANE SELECT
NM_001128425.2:c.44T>C
NM_001293190.2:c.44T>C
NM_001293191.2:c.2T>C
NM_001293192.2:c.-211T>C
NM_001293195.2:c.2T>C
NM_001293196.2:c.-211T>C
NM_001350650.2:c.-270T>C
NM_001350651.2:c.-206T>C
NM_012222.3:c.44T>C
NP_001041636.2:p.Met1Thr
NP_001041637.1:p.Met1Thr
NP_001041638.1:p.Met1Thr
NP_001041639.1:p.Met1Thr
NP_001121897.1:p.Met15Thr
NP_001121897.1:p.Met15Thr
NP_001280119.1:p.Met15Thr
NP_001280120.1:p.Met1Thr
NP_001280124.1:p.Met1Thr
NP_036354.1:p.Met15Thr
LRG_220t1:c.44T>C
LRG_220:g.10967T>C
LRG_220p1:p.Met15Thr
NC_000001.10:g.45800176A>G
NM_001128425.1:c.44T>C
NR_146882.2:n.230T>C
NR_146883.2:n.153T>C

Protein change:

M15T

Links:

dbSNP: rs201163858

NCBI 1000 Genomes Browser:

rs201163858

Molecular consequence:

NM_001293192.2:c.-211T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-211T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-270T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-206T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048172.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048173.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048174.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001293191.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001293195.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048171.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.230T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.153T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545767	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24691292, 28492532
SCV002030126	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 13, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004835759	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545767

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 22, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002030126

Baylor Genetics - CSER-TexasKidsCanSeq

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 13, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004835759

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype.

Seguí N, Navarro M, Pineda M, Köger N, Bellido F, González S, Campos O, Iglesias S, Valdés-Mas R, López-Doriga A, Gut M, Blanco I, Lázaro C, Capellá G, Puente XS, Plotz G, Valle L.

Gut. 2015 Feb;64(2):355-6. doi: 10.1136/gutjnl-2014-307084. Epub 2014 Apr 1. No abstract available.

PubMed [citation]

PMID:: 24691292

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000545767.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 15 of the MUTYH protein (p.Met15Thr). This variant is present in population databases (rs201163858, 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: 406849). 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. This variant disrupts the p.Met15 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24691292). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV002030126.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004835759.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces methionine with threonine at codon 15 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 breast cancer (PMID: 33471991). This variant has been identified in 2/251474 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine