NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe) AND Familial adenomatous polyposis 2

Germline classification:: Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:: Jan 4, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000123154.24

Allele description [Variation Report for NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe)]

NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe)

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.652G>T (p.Val218Phe)

Other names:

p.V246F:GTC>TTC

HGVS:

NC_000001.11:g.45332443C>A
NG_008189.1:g.13028G>T
NM_001048171.2:c.652G>T
NM_001048172.2:c.655G>T
NM_001048173.2:c.652G>T
NM_001048174.2:c.652G>TMANE SELECT
NM_001128425.2:c.736G>T
NM_001293190.2:c.697G>T
NM_001293191.2:c.685G>T
NM_001293192.2:c.376G>T
NM_001293195.2:c.652G>T
NM_001293196.2:c.376G>T
NM_001350650.2:c.307G>T
NM_001350651.2:c.307G>T
NM_012222.3:c.727G>T
NP_001041636.1:p.Val232Phe
NP_001041636.2:p.Val218Phe
NP_001041637.1:p.Val219Phe
NP_001041638.1:p.Val218Phe
NP_001041639.1:p.Val218Phe
NP_001121897.1:p.Val246Phe
NP_001121897.1:p.Val246Phe
NP_001280119.1:p.Val233Phe
NP_001280120.1:p.Val229Phe
NP_001280121.1:p.Val126Phe
NP_001280124.1:p.Val218Phe
NP_001280125.1:p.Val126Phe
NP_001337579.1:p.Val103Phe
NP_001337580.1:p.Val103Phe
NP_036354.1:p.Val243Phe
LRG_220t1:c.736G>T
LRG_220:g.13028G>T
LRG_220p1:p.Val246Phe
NC_000001.10:g.45798115C>A
NM_001048171.1:c.694G>T
NM_001128425.1:c.736G>T
NM_001128425.2:c.736G>T
NR_146882.2:n.880G>T
NR_146883.2:n.729G>T
p.V246F

Protein change:

V103F

Links:

dbSNP: rs587780749

NCBI 1000 Genomes Browser:

rs587780749

Molecular consequence:

NM_001048171.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.655G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.736G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.697G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.685G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.376G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.376G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.307G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.307G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.727G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.880G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.729G>T - 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
SCV000166458	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12606733, 19793053, 20687945, 15673720, 18534194, 28492532
SCV000357899	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Uncertain significance (Jun 14, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15673720, 12606733, 20687945, 19531215, 25820570 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000487315	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Dec 1, 2015)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20687945, 19793053, 19531215, 24733792, 25820570, 12606733, 15673720 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000837763	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV002512279	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580493	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004100060	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 3, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25820570, 20687945, 26377631, 12606733, 18534194, 24733792, 35264596, 15673720, 19793053 Citation Link,
SCV004198882	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?

Gómez-Fernández N, Castellví-Bel S, Fernández-Rozadilla C, Balaguer F, Muñoz J, Madrigal I, Milà M, Graña B, Vega A, Castells A, Carracedo A, Ruiz-Ponte C.

BMC Med Genet. 2009 Jun 16;10:57. doi: 10.1186/1471-2350-10-57.

PubMed [citation]

PMID:: 19531215
PMCID:: PMC2702373

See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000166458.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 246 of the MUTYH protein (p.Val246Phe). This variant is present in population databases (rs587780749, gnomAD 0.04%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 12606733, 19793053, 20687945). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.694G>T, p.Val232Phe. ClinVar contains an entry for this variant (Variation ID: 135990). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15673720, 18534194). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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 Illumina Laboratory Services, Illumina, SCV000357899.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.694G>T (p.Val232Phe) variant has been reported in three studies and is found in three patients with MYH-associated polyposis, including two in a compound heterozygous state and in one patient allele where zygosity was not specified (Seiber et al. 2003; Gomez-Fernandez et al. 2009; Lopez-Villar et al. 2010). The p.Val232Phe variant was absent from at least 107 controls but is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium, but this is based on one allele in an area of poor sequence coverage. Two studies have provided in vitro functional analysis in E. coli cells, and the results were somewhat conflicting. Bai et al. (2005) demonstrated that the p.Val232Phe variant resulted in an 89% reduction in glycosylase activity compared to wild type after adjusting for protein concentrations. Additionally, in cells transfected with the p.Val232Phe variant, DNA binding affinity of MYH was reduced to approximately two percent compared with the wild type enzyme. However, Komine et al. (2015) utilized a different E. coli complementation method and concluded that the functionality of the p.Val232Phe variant was retained compared to wild type. Taking into consideration both the patient data and conflicting functional evidence, the p.Val232Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for MYH-associated polyposis.

#	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 Counsyl, SCV000487315.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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

From Mendelics, SCV000837763.2

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

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512279.1

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

Description

ACMG classification criteria: PS4 moderate

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

From MGZ Medical Genetics Center, SCV002580493.1

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

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100060.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: MUTYH c.736G>T (p.Val246Phe) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.736G>T has been reported in the literature as p.Val232Phe or p.Val246Phe in a biallelic genotype in at-least three individuals affected with features of MUTYH-associated polyposis (example, Sieber_2003, Lopez-Villar_2010, Filpe_2009) and has also been reported as a presumed heterozygous monoallelic occurrence in settings of multigene panel testing (example, Kurian_2014, Guindalini_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 11% of normal DNA glycosylase activity (Bai_2005) while another study characterized this as "functionally retained" attributing the discrepancy to different E. coli backgrounds in the experimental system utilized (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 18534194, 15673720, 26377631, 19793053, 35264596, 25820570, 24733792, 20687945, 12606733). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=2; LP, n=10). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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, SCV004198882.1

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

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

Last Updated: May 7, 2024

Relating variation to medicine