NM_001048171.1(MUTYH):c.1259C>T (p.Thr420Met) AND MYH-associated polyposis

Clinical significance:Uncertain significance (Last evaluated: Oct 23, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000411291.7

Allele description [Variation Report for NM_001048171.1(MUTYH):c.1259C>T (p.Thr420Met)]

NM_001048171.1(MUTYH):c.1259C>T (p.Thr420Met)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048171.1(MUTYH):c.1259C>T (p.Thr420Met)
Other names:
p.T434M:ACG>ATG
HGVS:
  • NC_000001.11:g.45331442G>A
  • NG_008189.1:g.14029C>T
  • NM_001048171.1:c.1259C>T
  • NM_001048172.1:c.1220C>T
  • NM_001048173.1:c.1217C>T
  • NM_001048174.1:c.1217C>T
  • NM_001128425.1:c.1301C>T
  • NM_001293190.1:c.1262C>T
  • NM_001293191.1:c.1250C>T
  • NM_001293192.1:c.941C>T
  • NM_001293195.1:c.1217C>T
  • NM_001293196.1:c.941C>T
  • NM_001350650.1:c.872C>T
  • NM_001350651.1:c.872C>T
  • NM_012222.2:c.1292C>T
  • NP_001041636.1:p.Thr420Met
  • NP_001041637.1:p.Thr407Met
  • NP_001041638.1:p.Thr406Met
  • NP_001041639.1:p.Thr406Met
  • NP_001121897.1:p.Thr434Met
  • NP_001280119.1:p.Thr421Met
  • NP_001280120.1:p.Thr417Met
  • NP_001280121.1:p.Thr314Met
  • NP_001280124.1:p.Thr406Met
  • NP_001280125.1:p.Thr314Met
  • NP_001337579.1:p.Thr291Met
  • NP_001337580.1:p.Thr291Met
  • NP_036354.1:p.Thr431Met
  • LRG_220t1:c.1301C>T
  • LRG_220:g.14029C>T
  • LRG_220p1:p.Thr434Met
  • NC_000001.10:g.45797114G>A
  • NR_146882.1:n.1475C>T
  • NR_146883.1:n.1289C>T
  • p.T434M
Protein change:
T291M
Links:
dbSNP: rs587780084
NCBI 1000 Genomes Browser:
rs587780084
Molecular consequence:
  • NM_001048171.1:c.1259C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.1:c.1220C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.1:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.1:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.1:c.1301C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.1:c.1262C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.1:c.1250C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.1:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.1:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.1:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.1:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.1:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.2:c.1292C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.1:n.1475C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.1:n.1289C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
MYH-associated polyposis (FAP2)
Synonyms:
COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; FAP type 2; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000487339Counsylcriteria provided, single submitter
Uncertain significance
(Mar 3, 2016)
unknownclinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000639269Invitaecriteria provided, single submitter
Uncertain significance
(Oct 23, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]
PMID:
24728327
PMCID:
PMC3984285

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]
PMID:
28135145
PMCID:
PMC5455355
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000487339.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000639269.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces threonine with methionine at codon 434 of the MUTYH protein (p.Thr434Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs587780084, ExAC 0.009%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) as well as in an individual undergoing Lynch syndrome genetic testing (PMID: 25980754). This variant is also known as c.1259C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 127837). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2021

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