NM_000249.4(MLH1):c.1744C>G (p.Leu582Val) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 11, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001193957.2

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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hypothetical protein VITISV_017889 [Vitis vinifera]
hypothetical protein VITISV_017889 [Vitis vinifera]
gi|147767344|emb|CAN71267.1|

Protein
Homo sapiens isolate csct_007799 mitochondrion, complete genome
Homo sapiens isolate csct_007799 mitochondrion, complete genome
gi|1150596863|gb|KY410222.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001363153	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12810663, 17510385, 10037723, 26332594, 7757073, 15864295, 31386297, 33309985, 36243179 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001363153

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Dec 11, 2023)

germline

clinical testing

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

Citation Link

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

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]

PMID:: 12810663

Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C.

Cancer Res. 2007 May 15;67(10):4595-604.

PubMed [citation]

PMID:: 17510385

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363153.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: MLH1 c.1744C>G (p.Leu582Val) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251262 control chromosomes (gnomAD) but was reported at a frequency of 0.001409 from 108604 chromosomes in ToMMo 54KJPN (jMorp variation ID0191aa67588b00000). c.1744C>G has been reported in the literature in at-least one family with Lynch Syndrome (Han_1995), individuals affected with various types of cancer (example: Kiyozumi_2019, Fuijita_2022,Okawa_2023) as well as in individuals from control study cohorts (example: Fuijita_2022, and Okawa_2023). Several publications report experimental evidence evaluating an impact on protein function. These results reproducibly reported no damaging effect of this variant on measures of interaction with PMS2, in-vitro MMR activity, and interaction with hMRE11 (Guerrette_1999, Takahashi_2007, Vo_2005, Kondo_2003). The following publications have been ascertained in the context of this evaluation (PMID: 10037723, 7757073, 12810663, 17510385, 15864295, 31386297, 26332594, 33309985, 36243179). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. 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

Last Updated: Sep 29, 2024

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