NM_001048174.2(MUTYH):c.1174C>A (p.Leu392Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: May 25, 2021
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:: RCV000115755.20

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1174C>A (p.Leu392Met)]

NM_001048174.2(MUTYH):c.1174C>A (p.Leu392Met)

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.1174C>A (p.Leu392Met)

Other names:

p.L420M:CTG>ATG

HGVS:

NC_000001.11:g.45331485G>T
NG_008189.1:g.13986C>A
NM_001048171.2:c.1174C>A
NM_001048172.2:c.1177C>A
NM_001048173.2:c.1174C>A
NM_001048174.2:c.1174C>AMANE SELECT
NM_001128425.2:c.1258C>A
NM_001293190.2:c.1219C>A
NM_001293191.2:c.1207C>A
NM_001293192.2:c.898C>A
NM_001293195.2:c.1174C>A
NM_001293196.2:c.898C>A
NM_001350650.2:c.829C>A
NM_001350651.2:c.829C>A
NM_012222.3:c.1249C>A
NP_001041636.1:p.Leu406Met
NP_001041636.2:p.Leu392Met
NP_001041637.1:p.Leu393Met
NP_001041638.1:p.Leu392Met
NP_001041639.1:p.Leu392Met
NP_001121897.1:p.Leu420Met
NP_001121897.1:p.Leu420Met
NP_001280119.1:p.Leu407Met
NP_001280120.1:p.Leu403Met
NP_001280121.1:p.Leu300Met
NP_001280124.1:p.Leu392Met
NP_001280125.1:p.Leu300Met
NP_001337579.1:p.Leu277Met
NP_001337580.1:p.Leu277Met
NP_036354.1:p.Leu417Met
NP_036354.1:p.Leu417Met
LRG_220t1:c.1258C>A
LRG_220:g.13986C>A
LRG_220p1:p.Leu420Met
NC_000001.10:g.45797157G>T
NM_001048171.1:c.1216C>A
NM_001128425.1:c.1258C>A
NM_012222.2:c.1249C>A
NR_146882.2:n.1402C>A
NR_146883.2:n.1251C>A
p.L420M

Protein change:

L277M

Links:

dbSNP: rs144079536

NCBI 1000 Genomes Browser:

rs144079536

Molecular consequence:

NM_001048171.2:c.1174C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1177C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1174C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1174C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1258C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1219C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1207C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.898C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1174C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.898C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.829C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.829C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1249C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1402C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1251C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187241	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (Jun 30, 2014)	germline	clinical testing	Citation Link,
SCV000267060	Vantari Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 25, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000679735	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000788061	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Oct 30, 2017)	germline	clinical testing
SCV000910570	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 21, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000987279	Center of Medical Genetics and Primary Health Care	no assertion criteria provided	Uncertain significance (Apr 8, 2020)	germline	research
SCV002532217	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely benign (May 25, 2021)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 16774938, 17949294, 20110747, 24470512, 28202063, 27829682, 29700634, 30564557, 30374176, 25820570 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	2	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

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

Increased frequency of disease-causing MYH mutations in colon cancer families.

Peterlongo P, Mitra N, Sanchez de Abajo A, de la Hoya M, Bassi C, Bertario L, Radice P, Glogowski E, Nafa K, Caldes T, Offit K, Ellis NA.

Carcinogenesis. 2006 Nov;27(11):2243-9. Epub 2006 Jun 14.

PubMed [citation]

PMID:: 16774938

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000187241.9

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

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Vantari Genetics, SCV000267060.1

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

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV000679735.1

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

From True Health Diagnostics, SCV000788061.1

#	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 Color Diagnostics, LLC DBA Color Health, SCV000910570.1

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

From Center of Medical Genetics and Primary Health Care, SCV000987279.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	not provided

Description

ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A domain DNA_Glycosylase_C (R354-483Y aa) involved in Adenine DNA glycosylation. Hot-spot has 24 non-VUS coding variants (12 PATH and 12 BEN), pathogenicity = 50.0%, proximity score 3.836 > threshold 2.472. PP2 Pathogenic Supporting: 59 out of 97 non-VUS missense variants in gene MUTYH are PATH = 60.8% > threshold of 51.0%, and 191 out of 1,184 clinically reported variants in gene MUTYH are PATH = 16.1% > threshold of 12.0%. PP3 Pathogenic Supporting: 7 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 4 benign predictions from DEOGEN2, EIGEN, PrimateAI and REVEL. PP4 Pathogenic Supporting: The variant was detected in two unrelated female patients diagnosed with bilateral breast cancer or breast and ovarian cancers both with strong family history of breast and ovarian cancer. BS3 Benign Strong: At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an assay evaluating base excision repair (BER) with a MutY-Deficient E Coli complementation assay (PMID: 25820570). 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.

#	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		2	not provided	2	not provided

From Sema4, Sema4, SCV002532217.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

#	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: Dec 22, 2024

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