NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jul 31, 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:: RCV000212715.36

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)]

NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)

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.1192C>T (p.Arg398Cys)

Other names:

p.R426C:CGT>TGT

HGVS:

NC_000001.11:g.45331467G>A
NG_008189.1:g.14004C>T
NM_001048171.2:c.1192C>T
NM_001048172.2:c.1195C>T
NM_001048173.2:c.1192C>T
NM_001048174.2:c.1192C>TMANE SELECT
NM_001128425.2:c.1276C>T
NM_001293190.2:c.1237C>T
NM_001293191.2:c.1225C>T
NM_001293192.2:c.916C>T
NM_001293195.2:c.1192C>T
NM_001293196.2:c.916C>T
NM_001350650.2:c.847C>T
NM_001350651.2:c.847C>T
NM_012222.3:c.1267C>T
NP_001041636.1:p.Arg412Cys
NP_001041636.2:p.Arg398Cys
NP_001041637.1:p.Arg399Cys
NP_001041638.1:p.Arg398Cys
NP_001041639.1:p.Arg398Cys
NP_001121897.1:p.Arg426Cys
NP_001121897.1:p.Arg426Cys
NP_001280119.1:p.Arg413Cys
NP_001280120.1:p.Arg409Cys
NP_001280121.1:p.Arg306Cys
NP_001280124.1:p.Arg398Cys
NP_001280125.1:p.Arg306Cys
NP_001337579.1:p.Arg283Cys
NP_001337580.1:p.Arg283Cys
NP_036354.1:p.Arg423Cys
NP_036354.1:p.Arg423Cys
LRG_220t1:c.1276C>T
LRG_220:g.14004C>T
LRG_220p1:p.Arg426Cys
NC_000001.10:g.45797139G>A
NM_001048171.1:c.1234C>T
NM_001048174.1:c.1192C>T
NM_001048174.2:c.1192C>T
NM_001128425.1:c.1276C>T
NM_012222.2:c.1267C>T
NR_146882.2:n.1420C>T
NR_146883.2:n.1269C>T
p.R426C

Protein change:

R283C

Links:

dbSNP: rs150792276

NCBI 1000 Genomes Browser:

rs150792276

Molecular consequence:

NM_001048171.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1237C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1267C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1420C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1269C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Astragalus uliginosus voucher MSB:993 18S ribosomal RNA gene, partial sequence; ...
Astragalus uliginosus voucher MSB:993 18S ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8 ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and 26S ribosomal RNA gene, partial sequence
gi|1215153913|gb|KX955045.1|

Nucleotide
Astragalus tribuloides voucher FUMH:30536 18S ribosomal RNA gene, partial sequen...
Astragalus tribuloides voucher FUMH:30536 18S ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8 ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and 26S ribosomal RNA gene, partial sequence
gi|1215153910|gb|KX955042.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697674	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 24, 2024)	germline	clinical testing	PubMed (27) [See all records that cite these PMIDs] 22703879, 25820570, 16134147, 16557584, 19531215, 24470512, 20687945, 17524638, 14991577, 26976419, 22976915, 27443514, 28135145, 28944238, 30256826, 30151275, 27829682, 30564557, 30850667, 31159747, 31921681, 31422818, 33383211, 33134171, 35089076, 35430768, 35628513 Citation Link,
SCV000711723	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 11, 2017)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 14579148, 16557584, 25980754, 16616356, 14991577, 19531215, 24470512, 22703879, 17524638, 21777424, 16134147, 20687945, 25820570, 26976419, 27829682, 24033266
SCV000885747	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely benign (Aug 29, 2018)	germline	clinical testing	Citation Link,
SCV002067654	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002552418	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 31, 2024)	germline	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and molecular features of attenuated adenomatous polyposis in northern Italy.

de Leon MP, Urso ED, Pucciarelli S, Agostini M, Nitti D, Roncucci L, Benatti P, Pedroni M, Kaleci S, Balsamo A, Laudi C, Di Gregorio C, Viel A, Rossi G, Venesio T.

Tech Coloproctol. 2013 Feb;17(1):79-87. doi: 10.1007/s10151-012-0887-5. Epub 2012 Sep 14.

PubMed [citation]

PMID:: 22976915

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort.

Ring KL, Bruegl AS, Allen BA, Elkin EP, Singh N, Hartman AR, Daniels MS, Broaddus RR.

Mod Pathol. 2016 Nov;29(11):1381-1389. doi: 10.1038/modpathol.2016.135. Epub 2016 Jul 22.

PubMed [citation]

PMID:: 27443514
PMCID:: PMC5541389

See all PubMed Citations (33)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697674.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (27)

Description

Variant summary: MUTYH c.1276C>T (p.Arg426Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 252980 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00081 vs 0.0046), allowing no conclusion about variant significance. c.1276C>T has been reported in multiple FAP or attenuated FAP patients in monoallelic state (e.g. Aceto_2005, Aretz_2006, de Lyon_2013, Ricci_2017, Sulova_2009). Furthermore, it has been reported with other pathogenic MUTYH variants in biallelic patients affected with synchronous/metachronous polyps (Lopez-Villar_2010) and colorectal cancer (e.g. De Rycke 2017, Yurgelun 2017). In some of these reports, it was classified as a VUS in settings of multigene cancer panel testing. Additional reports of the variant in individuals with a personal and/or family history of colorectal cancer, HBOC, lung and endometrial cancer have also been published (e.g. Fleischmann_2004, Ricci_2016, Ring_2016, Tung_2016, Martin-Morales_2018, Rizzolo_2018, Oliver_2019, Lin_2019, Tsaousis_2019, Grasel_2020, Pope_2021, Sahin_2022). These data do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA2 c.4647_4650delAGAG , p.Lys1549fsX18 ; APC c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; MSH6 c.3013C>T, p.Arg1005X; PALB2 c.2386G>T, p.Gly796X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by comparable function to wild-type in terms of suppression of spontaneous mutations (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25820570, 16134147, 16557584, 19531215, 24470512, 20687945, 17524638, 14991577, 26976419, 22976915, 27443514, 28135145, 28944238, 30256826, 30151275, 27829682, 30564557, 30850667, 31159747, 31921681, 31422818, 33383211, 33134171, 35089076, 35430768, 35628513). ClinVar contains an entry for this variant (Variation ID: 41753). Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711723.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (16)

Description

The p.Arg426Cys variant in MUTYH has been reported in at > 8 individuals with co lorectal cancer (Aceto 2005, Aretz 2006, Sulova 2007, Gomez-Fernadez 2009, Lopez -Villar 2010, Guarinos 2014, Yurgelun 2015, Ricci 2017), 2 individuals with brea st cancer (Tung 2016), 1 individual with lung cancer (Al-Tassan 2004) and has a lso been reported by other clinical laboratories in ClinVar (Variation ID 41753) . All individuals reported in the literature were heterozygous and did not carry a second MUTYH variant. This variant has also been identified in 0.1% (184/1266 06) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Althou gh this variant has been seen in the general population, its frequency is not hi gh enough to rule out a pathogenic role. In vitro functional studies provide som e evidence that the p.Arg426Cys variant may not impact protein function (Komine 2015) and computational prediction tools and conservation analysis suggest that the p.Arg426Cys variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of the p.Arg426Cys variant is uncertain. ACMG/AMP Criteria applied: BP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885747.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002067654.1

#	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.1276C>T, in exon 13 that results in an amino acid change, p.Arg426Cys. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the non-Finnish European sub-population (dbSNP rs150792276). The p.Arg426Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg426Cys substitution. The p.Arg426Cys sequence change has been reported in the heterozygous state in multiple individuals with colorectal cancer (PMIDs: 16134147, 16557584, 17524638, 19531215, 20687945, 24470512, 25980754), two individuals with breast cancer (PMID: 26976419), and one individual with lung cancer (PMID: 14579148). Functional studies using a yeast complementation assay demonstrated that MUTYH p.Arg426Cys had base excision repair activity similar to wild-type (PMID: 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg426Cys 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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002552418.5

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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