NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 1, 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:: RCV001818275.7

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]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002070313	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002598690	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 1, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25980754, 28135145, 33471991, 36243179 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002070313

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 30, 2020)

germline

clinical testing

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

SCV002598690

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 1, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

See all PubMed Citations (5)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002070313.1

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

Description

DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1301C>T, in exon 13 that results in an amino acid change, p.Thr434Met. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.004% (dbSNP rs587780084). Also known as c.1259C>T in the literature, this sequence change has been reported in an individual with colorectal cancer (PMID:28135145) and an individual with suspected Lynch syndrome (PMID: 25980754). The p.Thr434Met change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. The p.Thr434Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr434Met change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598690.3

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

Description

Variant summary: MUTYH c.1301C>T (p.Thr434Met) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of 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 4.3e-05 in 326508 control chromosomes (gnomAD and Okawa_2023). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1301C>T (aka c.1259C>T (p.Thr420Met)) has been reported in the literature in the heterozygous state in an individual affected with suspected Lynch syndrome and/or polyps (Yurgelun_2015), and in a patient with colorectal cancer (Yurgelun_2017). The variant was also reported in a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), in 9/60466 cases, and in 5/53461 controls (Dorling_2021 through LOVD). These reports 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: 33471991, 36243179, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127837). Based on the evidence outlined above, the variant was classified as 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

Last Updated: Sep 29, 2024

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