NM_000249.4(MLH1):c.1081A>G (p.Lys361Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 6, 2022
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:: RCV000164376.5

Allele description [Variation Report for NM_000249.4(MLH1):c.1081A>G (p.Lys361Glu)]

NM_000249.4(MLH1):c.1081A>G (p.Lys361Glu)

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.1081A>G (p.Lys361Glu)

HGVS:

NC_000003.12:g.37025679A>G
NG_007109.2:g.37330A>G
NM_000249.4:c.1081A>GMANE SELECT
NM_001167617.3:c.787A>G
NM_001167618.3:c.358A>G
NM_001167619.3:c.358A>G
NM_001258271.2:c.1081A>G
NM_001258273.2:c.358A>G
NM_001258274.3:c.358A>G
NM_001354615.2:c.358A>G
NM_001354616.2:c.358A>G
NM_001354617.2:c.358A>G
NM_001354618.2:c.358A>G
NM_001354619.2:c.358A>G
NM_001354620.2:c.787A>G
NM_001354621.2:c.58A>G
NM_001354622.2:c.58A>G
NM_001354623.2:c.58A>G
NM_001354624.2:c.7A>G
NM_001354625.2:c.7A>G
NM_001354626.2:c.7A>G
NM_001354627.2:c.7A>G
NM_001354628.2:c.1081A>G
NM_001354629.2:c.982A>G
NM_001354630.2:c.1081A>G
NP_000240.1:p.Lys361Glu
NP_000240.1:p.Lys361Glu
NP_001161089.1:p.Lys263Glu
NP_001161090.1:p.Lys120Glu
NP_001161091.1:p.Lys120Glu
NP_001245200.1:p.Lys361Glu
NP_001245202.1:p.Lys120Glu
NP_001245203.1:p.Lys120Glu
NP_001341544.1:p.Lys120Glu
NP_001341545.1:p.Lys120Glu
NP_001341546.1:p.Lys120Glu
NP_001341547.1:p.Lys120Glu
NP_001341548.1:p.Lys120Glu
NP_001341549.1:p.Lys263Glu
NP_001341550.1:p.Lys20Glu
NP_001341551.1:p.Lys20Glu
NP_001341552.1:p.Lys20Glu
NP_001341553.1:p.Lys3Glu
NP_001341554.1:p.Lys3Glu
NP_001341555.1:p.Lys3Glu
NP_001341556.1:p.Lys3Glu
NP_001341557.1:p.Lys361Glu
NP_001341558.1:p.Lys328Glu
NP_001341559.1:p.Lys361Glu
LRG_216t1:c.1081A>G
LRG_216:g.37330A>G
LRG_216p1:p.Lys361Glu
NC_000003.11:g.37067170A>G
NM_000249.3:c.1081A>G
p.K361E

Protein change:

K120E

Links:

dbSNP: rs786201875

NCBI 1000 Genomes Browser:

rs786201875

Molecular consequence:

NM_000249.4:c.1081A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.787A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1081A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.787A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.58A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.58A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.58A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.7A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.7A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.7A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.7A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1081A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.982A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1081A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000215011	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Apr 6, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002528620	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Nov 12, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215011

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Apr 6, 2022)

germline

clinical testing

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

Citation Link,

SCV002528620

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Nov 12, 2021)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

HDAC6 regulates DNA damage response via deacetylating MLH1.

Zhang M, Hu C, Moses N, Haakenson J, Xiang S, Quan D, Fang B, Yang Z, Bai W, Bepler G, Li GM, Zhang XM.

J Biol Chem. 2019 Apr 12;294(15):5813-5826. doi: 10.1074/jbc.RA118.006374. Epub 2019 Feb 15.

PubMed [citation]

PMID:: 30770470
PMCID:: PMC6463726

Details of each submission

From Ambry Genetics, SCV000215011.6

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

Description

The p.K361E variant (also known as c.1081A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide position 1081. The lysine at codon 361 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	1	not provided	not provided		1	not provided	not provided	not provided

From Sema4, Sema4, SCV002528620.1

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

Last Updated: Apr 20, 2024

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