NM_000249.4(MLH1):c.1744C>G (p.Leu582Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 8, 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:: RCV000571505.10

Allele description [Variation Report for NM_000249.4(MLH1):c.1744C>G (p.Leu582Val)]

NM_000249.4(MLH1):c.1744C>G (p.Leu582Val)

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.1744C>G (p.Leu582Val)

HGVS:

NC_000003.12:g.37047531C>G
NG_007109.2:g.59182C>G
NM_000249.4:c.1744C>GMANE SELECT
NM_001167617.3:c.1450C>G
NM_001167618.3:c.1021C>G
NM_001167619.3:c.1021C>G
NM_001258271.2:c.1744C>G
NM_001258273.2:c.1021C>G
NM_001258274.3:c.1021C>G
NM_001354615.2:c.1021C>G
NM_001354616.2:c.1021C>G
NM_001354617.2:c.1021C>G
NM_001354618.2:c.1021C>G
NM_001354619.2:c.1021C>G
NM_001354620.2:c.1450C>G
NM_001354621.2:c.721C>G
NM_001354622.2:c.721C>G
NM_001354623.2:c.721C>G
NM_001354624.2:c.670C>G
NM_001354625.2:c.670C>G
NM_001354626.2:c.670C>G
NM_001354627.2:c.670C>G
NM_001354628.2:c.1744C>G
NM_001354629.2:c.1645C>G
NM_001354630.2:c.1732-986C>G
NP_000240.1:p.Leu582Val
NP_000240.1:p.Leu582Val
NP_001161089.1:p.Leu484Val
NP_001161090.1:p.Leu341Val
NP_001161091.1:p.Leu341Val
NP_001245200.1:p.Leu582Val
NP_001245202.1:p.Leu341Val
NP_001245203.1:p.Leu341Val
NP_001341544.1:p.Leu341Val
NP_001341545.1:p.Leu341Val
NP_001341546.1:p.Leu341Val
NP_001341547.1:p.Leu341Val
NP_001341548.1:p.Leu341Val
NP_001341549.1:p.Leu484Val
NP_001341550.1:p.Leu241Val
NP_001341551.1:p.Leu241Val
NP_001341552.1:p.Leu241Val
NP_001341553.1:p.Leu224Val
NP_001341554.1:p.Leu224Val
NP_001341555.1:p.Leu224Val
NP_001341556.1:p.Leu224Val
NP_001341557.1:p.Leu582Val
NP_001341558.1:p.Leu549Val
LRG_216t1:c.1744C>G
LRG_216:g.59182C>G
LRG_216p1:p.Leu582Val
NC_000003.11:g.37089022C>G
NM_000249.3:c.1744C>G
P40692:p.Leu582Val

Protein change:

L224V

Links:

UniProtKB: P40692#VAR_004460; dbSNP: rs63751713

NCBI 1000 Genomes Browser:

rs63751713

Molecular consequence:

NM_001354630.2:c.1732-986C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1744C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1450C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1744C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1021C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1450C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.721C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.721C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.721C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.670C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.670C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.670C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.670C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1744C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1645C>G - 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
SCV000662046	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 16, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10037723, 12810663, 15864295, 16995940, 17510385, 23760103, 32206572, 33309985, 7757073, 9697702 Citation Link,
SCV000908644	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 8, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 7757073, 9697702, 10037723, 12810663, 15864295, 17510385, 21064154, 29050249, 29192238, 32206572, 33309985, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000662046

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 16, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000908644

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 8, 2023)

germline

clinical testing

PubMed (12)
[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

In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects.

Lastella P, Surdo NC, Resta N, Guanti G, Stella A.

BMC Genomics. 2006 Sep 22;7:243.

PubMed [citation]

PMID:: 16995940
PMCID:: PMC1590028

Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.

Zhu M, Chen HM, Wang YP.

Oncol Lett. 2013 May;5(5):1710-1718. Epub 2013 Mar 11.

PubMed [citation]

PMID:: 23760103
PMCID:: PMC3678577

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000662046.6

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

Description

The p.L582V variant (also known as c.1744C>G), located in coding exon 16 of the MLH1 gene, results from a C to G substitution at nucleotide position 1744. The leucine at codon 582 is replaced by valine, an amino acid with highly similar properties. This variant was identified in an individual meeting Amsterdam II criteria and the mismatch repair (MMR) activity for the variant was either gone or reduced in a functional assay using yeast (Shimodaira H et al. Nat. Genet. 1998 Aug;19(4):384-9). However, several studies have demonstrated expression levels, PMS2 binding, and MMR activity were similar to that of wild type MLH1 (Guerrette S et al., J. Biol. Chem. 1999 Mar; 274(10):6336-41; Kondo E et al., Cancer Res. 2003 Jun; 63(12):3302-8;Takahashi M et al., Cancer Res. 2007 May; 67(10):4595-604; Vo AT et al., EMBO Rep. 2005 May; 6(5):438-44). This variant has been identified in 45/12503 unselected Japanese colorectal cancer patients and in 102/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This amino acid position is highly 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, SCV000908644.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces leucine with valine at codon 582 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant retained 93% of wild type MLH1 mismatch repair activity via yeast-2-hybrid and mismatch repair activity assays (PMID: 17510385, 15864295, 12810663, 10037723, 9697702, 21064154). Other functional studies reported altered protein interaction with mismatch repair machinery and loss of dominant mutator effect via yeast-2-hybrid and dominant mutator assays (PMID: 9697702, 15864295). This variant has been reported in individuals affected with Lynch syndrome, colorectal cancer, gastric cancer and mesothelioma (PMID: 7757073, 9697702, 17510385, 29050249, 29192238, 32206572, 33309985). This variant has been identified in 1/246040 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been observed in over one hundred individuals from a healthy control population (PMID: 33309985). 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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