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NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met) AND Familial adenomatous polyposis 2

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Jan 26, 2024
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:
RCV000411291.16

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)]

NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)

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.1217C>T (p.Thr406Met)
Other names:
p.T434M:ACG>ATG
HGVS:
  • NC_000001.11:g.45331442G>A
  • NG_008189.1:g.14029C>T
  • NM_001048171.2:c.1217C>T
  • NM_001048172.2:c.1220C>T
  • NM_001048173.2:c.1217C>T
  • NM_001048174.2:c.1217C>TMANE SELECT
  • NM_001128425.2:c.1301C>T
  • NM_001293190.2:c.1262C>T
  • NM_001293191.2:c.1250C>T
  • NM_001293192.2:c.941C>T
  • NM_001293195.2:c.1217C>T
  • NM_001293196.2:c.941C>T
  • NM_001350650.2:c.872C>T
  • NM_001350651.2:c.872C>T
  • NM_012222.3:c.1292C>T
  • NP_001041636.1:p.Thr420Met
  • NP_001041636.2:p.Thr406Met
  • NP_001041637.1:p.Thr407Met
  • NP_001041638.1:p.Thr406Met
  • NP_001041639.1:p.Thr406Met
  • NP_001121897.1:p.Thr434Met
  • 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
  • NM_001048171.1:c.1259C>T
  • NM_001128425.1:c.1301C>T
  • NR_146882.2:n.1445C>T
  • NR_146883.2:n.1294C>T
  • p.T434M
Protein change:
T291M
Links:
dbSNP: rs587780084
NCBI 1000 Genomes Browser:
rs587780084
Molecular consequence:
  • NM_001048171.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.1220C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.1301C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.1262C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.1250C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.1292C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.1445C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.1294C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
7

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000487339Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))
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,

SCV000639269Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 26, 2024)
germlineclinical testing

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

SCV004841115All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Nov 28, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown7not providednot provided108544not 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

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 (5)

Details of each submission

From Counsyl, SCV000487339.2

#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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000639269.9

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 434 of the MUTYH protein (p.Thr434Met). This variant is present in population databases (rs587780084, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 25980754, 28135145). This variant is also known as c.1259C>T (p.Thr420Met). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

From All of Us Research Program, National Institutes of Health, SCV004841115.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided7not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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 suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided7not providednot providednot provided

Last Updated: Sep 29, 2024