NM_001048174.2(MUTYH):c.1424G>A (p.Gly475Glu) AND not specified

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Sep 23, 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:: RCV000121600.21

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1424G>A (p.Gly475Glu)]

NM_001048174.2(MUTYH):c.1424G>A (p.Gly475Glu)

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.1424G>A (p.Gly475Glu)

Other names:

p.G503E:GGG>GAG

HGVS:

NC_000001.11:g.45330526C>T
NG_008189.1:g.14945G>A
NM_001048171.2:c.1424G>A
NM_001048172.2:c.1427G>A
NM_001048173.2:c.1424G>A
NM_001048174.2:c.1424G>AMANE SELECT
NM_001128425.2:c.1508G>A
NM_001293190.2:c.1469G>A
NM_001293191.2:c.1457G>A
NM_001293192.2:c.1148G>A
NM_001293195.2:c.1424G>A
NM_001293196.2:c.1148G>A
NM_001350650.2:c.1079G>A
NM_001350651.2:c.1079G>A
NM_012222.3:c.1499G>A
NP_001041636.1:p.Gly489Glu
NP_001041636.2:p.Gly475Glu
NP_001041637.1:p.Gly476Glu
NP_001041638.1:p.Gly475Glu
NP_001041639.1:p.Gly475Glu
NP_001121897.1:p.Gly503Glu
NP_001121897.1:p.Gly503Glu
NP_001280119.1:p.Gly490Glu
NP_001280120.1:p.Gly486Glu
NP_001280121.1:p.Gly383Glu
NP_001280124.1:p.Gly475Glu
NP_001280125.1:p.Gly383Glu
NP_001337579.1:p.Gly360Glu
NP_001337580.1:p.Gly360Glu
NP_036354.1:p.Gly500Glu
LRG_220t1:c.1508G>A
LRG_220:g.14945G>A
LRG_220p1:p.Gly503Glu
NC_000001.10:g.45796198C>T
NM_001048171.1:c.1466G>A
NM_001128425.1:c.1508G>A
NM_001128425.2:c.1508G>A
NR_146882.2:n.1652G>A
NR_146883.2:n.1501G>A
p.G503E

Protein change:

G360E

Links:

dbSNP: rs3219494

NCBI 1000 Genomes Browser:

rs3219494

Molecular consequence:

NM_001048171.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1427G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1508G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1469G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.1079G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.1079G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1499G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1652G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1501G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000085797	ITMI	no classification provided	not provided	germline	reference population	PubMed (1) [See all records that cite this PMID]
SCV000697681	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 23, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24728327, 25980754, 25820570, 25186627, 26689913, 35264596, 34816434, 32868316, 35534704 Citation Link,
SCV000966236	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jul 25, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25980754, 25820570, 24728327, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000085797

ITMI

no classification provided

not provided

germline

reference population

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

SCV000697681

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 23, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000966236

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jul 25, 2018)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
African	germline	unknown	not provided	not provided	not provided	43	not provided	reference population
African_European	germline	unknown	not provided	not provided	not provided	46	not provided	reference population
Central_Asian	germline	unknown	not provided	not provided	not provided	50	not provided	reference population
East_Asian	germline	unknown	not provided	not provided	not provided	62	not provided	reference population
European	germline	unknown	not provided	not provided	not provided	331	not provided	reference population
Hispanic	germline	unknown	not provided	not provided	not provided	118	not provided	reference population
Whole_cohort	germline	unknown	not provided	not provided	not provided	681	not provided	reference population

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

See all PubMed Citations (10)

Details of each submission

From ITMI, SCV000085797.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African	not provided	not provided	not provided	reference population	PubMed (1)
2	African_European	not provided	not provided	not provided	reference population	PubMed (1)
3	Central_Asian	not provided	not provided	not provided	reference population	PubMed (1)
4	East_Asian	not provided	not provided	not provided	reference population	PubMed (1)
5	European	not provided	not provided	not provided	reference population	PubMed (1)
6	Hispanic	not provided	not provided	not provided	reference population	PubMed (1)
7	Whole_cohort	not provided	not provided	not provided	reference population	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	43	not provided	discovery		not provided	0.0116	not provided	not provided
2	germline	unknown	46	not provided	discovery		not provided	0	not provided	not provided
3	germline	unknown	50	not provided	discovery		not provided	0	not provided	not provided
4	germline	unknown	62	not provided	discovery		not provided	0	not provided	not provided
5	germline	unknown	331	not provided	discovery		not provided	0	not provided	not provided
6	germline	unknown	118	not provided	discovery		not provided	0	not provided	not provided
7	germline	unknown	681	not provided	discovery		not provided	0.0007	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697681.6

#	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.1508G>A (p.Gly503Glu) results in a non-conservative amino acid change in 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 0.00013 in 243210 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00013 vs 0.0046), allowing no conclusion about variant significance. c.1508G>A has been reported in the literature in colorectal/breast cancer cases and in the TGCA cohort (e.g. Yurgelun_2015, Lu_2015, Tung_2015, Purrington_2020, Barreiro_2022, Guindalini_2022, de Oliveria_2022). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication has reported experimental evidence evaluating an impact on protein function and found the variant caused a partial defect in an E.coli model system (Komine 2015). The following publications have been ascertained in the context of this evaluation (PMID: 34816434, 24728327, 35264596, 25820570, 26689913, 32868316, 25186627, 25980754, 35534704). ClinVar contains an entry for this variant (Variation ID: 134866). 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966236.1

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

Description

The p.Gly503Glu variant in MUTYH has been reported in one individual with clinic al features of Lynch Syndrome as well as in one young reportedly healthy individ ual (Bodian 2014). This variant has also been reported by other clinical laborat ories in Clinvar (Variation ID: 134866) and has been identified in 0.22% (51/231 22) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs3219494). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. In vitro functional studies provide some evidence that the p.Gly503Glu variant may impact protein function (Komine 2015). Additionally, computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Gly503Glu variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting.

#	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		1	not provided	1	not provided

Last Updated: Jan 13, 2025

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