NM_000249.4(MLH1):c.1732G>A (p.Glu578Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 9, 2023
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:: RCV000570899.8

Allele description [Variation Report for NM_000249.4(MLH1):c.1732G>A (p.Glu578Lys)]

NM_000249.4(MLH1):c.1732G>A (p.Glu578Lys)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1732G>A (p.Glu578Lys)

HGVS:

NC_000003.12:g.37047519G>A
NG_007109.2:g.59170G>A
NM_000249.4:c.1732G>AMANE SELECT
NM_001167617.3:c.1438G>A
NM_001167618.3:c.1009G>A
NM_001167619.3:c.1009G>A
NM_001258271.2:c.1732G>A
NM_001258273.2:c.1009G>A
NM_001258274.3:c.1009G>A
NM_001354615.2:c.1009G>A
NM_001354616.2:c.1009G>A
NM_001354617.2:c.1009G>A
NM_001354618.2:c.1009G>A
NM_001354619.2:c.1009G>A
NM_001354620.2:c.1438G>A
NM_001354621.2:c.709G>A
NM_001354622.2:c.709G>A
NM_001354623.2:c.709G>A
NM_001354624.2:c.658G>A
NM_001354625.2:c.658G>A
NM_001354626.2:c.658G>A
NM_001354627.2:c.658G>A
NM_001354628.2:c.1732G>A
NM_001354629.2:c.1633G>A
NM_001354630.2:c.1732-998G>A
NP_000240.1:p.Glu578Lys
NP_000240.1:p.Glu578Lys
NP_001161089.1:p.Glu480Lys
NP_001161090.1:p.Glu337Lys
NP_001161091.1:p.Glu337Lys
NP_001245200.1:p.Glu578Lys
NP_001245202.1:p.Glu337Lys
NP_001245203.1:p.Glu337Lys
NP_001341544.1:p.Glu337Lys
NP_001341545.1:p.Glu337Lys
NP_001341546.1:p.Glu337Lys
NP_001341547.1:p.Glu337Lys
NP_001341548.1:p.Glu337Lys
NP_001341549.1:p.Glu480Lys
NP_001341550.1:p.Glu237Lys
NP_001341551.1:p.Glu237Lys
NP_001341552.1:p.Glu237Lys
NP_001341553.1:p.Glu220Lys
NP_001341554.1:p.Glu220Lys
NP_001341555.1:p.Glu220Lys
NP_001341556.1:p.Glu220Lys
NP_001341557.1:p.Glu578Lys
NP_001341558.1:p.Glu545Lys
LRG_216t1:c.1732G>A
LRG_216:g.59170G>A
LRG_216p1:p.Glu578Lys
NC_000003.11:g.37089010G>A
NM_000249.3:c.1732G>A

Protein change:

E220K

Links:

dbSNP: rs863224635

NCBI 1000 Genomes Browser:

rs863224635

Molecular consequence:

NM_001354630.2:c.1732-998G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1438G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1438G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.709G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.709G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.709G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1633G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000664833	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 1, 2023)	germline	clinical testing	Citation Link,
SCV001351188	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31391288, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000664833

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 1, 2023)

germline

clinical testing

Citation Link,

SCV001351188

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 9, 2023)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

Li S, Qian D, Thompson BA, Gutierrez S, Wu S, Pesaran T, LaDuca H, Lu HM, Chao EC, Black MH.

J Med Genet. 2020 Jan;57(1):62-69. doi: 10.1136/jmedgenet-2019-106096. Epub 2019 Aug 7.

PubMed [citation]

PMID:: 31391288

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

Details of each submission

From Ambry Genetics, SCV000664833.6

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

Description

The p.E578K variant (also known as c.1732G>A) is located in coding exon 16 of the MLH1 gene. The glutamic acid at codon 578 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001351188.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glutamic acid with lysine at codon 578 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 1/251236 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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