NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 20, 2017
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:: RCV000781534.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe)]

NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe)

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>T (p.Leu582Phe)

HGVS:

NC_000003.12:g.37047531C>T
NG_007109.2:g.59182C>T
NM_000249.4:c.1744C>TMANE SELECT
NM_001167617.3:c.1450C>T
NM_001167618.3:c.1021C>T
NM_001167619.3:c.1021C>T
NM_001258271.2:c.1744C>T
NM_001258273.2:c.1021C>T
NM_001258274.3:c.1021C>T
NM_001354615.2:c.1021C>T
NM_001354616.2:c.1021C>T
NM_001354617.2:c.1021C>T
NM_001354618.2:c.1021C>T
NM_001354619.2:c.1021C>T
NM_001354620.2:c.1450C>T
NM_001354621.2:c.721C>T
NM_001354622.2:c.721C>T
NM_001354623.2:c.721C>T
NM_001354624.2:c.670C>T
NM_001354625.2:c.670C>T
NM_001354626.2:c.670C>T
NM_001354627.2:c.670C>T
NM_001354628.2:c.1744C>T
NM_001354629.2:c.1645C>T
NM_001354630.2:c.1732-986C>T
NP_000240.1:p.Leu582Phe
NP_000240.1:p.Leu582Phe
NP_001161089.1:p.Leu484Phe
NP_001161090.1:p.Leu341Phe
NP_001161091.1:p.Leu341Phe
NP_001245200.1:p.Leu582Phe
NP_001245202.1:p.Leu341Phe
NP_001245203.1:p.Leu341Phe
NP_001341544.1:p.Leu341Phe
NP_001341545.1:p.Leu341Phe
NP_001341546.1:p.Leu341Phe
NP_001341547.1:p.Leu341Phe
NP_001341548.1:p.Leu341Phe
NP_001341549.1:p.Leu484Phe
NP_001341550.1:p.Leu241Phe
NP_001341551.1:p.Leu241Phe
NP_001341552.1:p.Leu241Phe
NP_001341553.1:p.Leu224Phe
NP_001341554.1:p.Leu224Phe
NP_001341555.1:p.Leu224Phe
NP_001341556.1:p.Leu224Phe
NP_001341557.1:p.Leu582Phe
NP_001341558.1:p.Leu549Phe
LRG_216t1:c.1744C>T
LRG_216:g.59182C>T
LRG_216p1:p.Leu582Phe
NC_000003.11:g.37089022C>T
NM_000249.3:c.1744C>T
P40692:p.Leu582Phe

Protein change:

L224F

Links:

UniProtKB: P40692#VAR_076349; dbSNP: rs63751713

NCBI 1000 Genomes Browser:

rs63751713

Molecular consequence:

NM_001354630.2:c.1732-986C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1645C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919640	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 20, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12547705, 17192056, 20020535, 22949387, 27435373, 18415027, 22753075 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919640

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 20, 2017)

germline

clinical testing

PubMed (7)
[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

Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors.

Hendriks Y, Franken P, Dierssen JW, De Leeuw W, Wijnen J, Dreef E, Tops C, Breuning M, Bröcker-Vriends A, Vasen H, Fodde R, Morreau H.

Am J Pathol. 2003 Feb;162(2):469-77.

PubMed [citation]

PMID:: 12547705
PMCID:: PMC1851154

The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome.

Lucci-Cordisco E, Boccuto L, Neri G, Genuardi M.

Cancer Biomark. 2006;2(1-2):11-27. Review.

PubMed [citation]

PMID:: 17192056

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: The MLH1 c.1744C>T (p.L582F) variant involves the alteration of a highly conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant. The variant is located within the PMS2/MLH3/PMS1 interaction domain and the abrogated interactions between MLH1 and PMS2 partners in addition to the variant being deficient in an MMR complementation assay were confirmed by functional studies (Drost_2009; Andersen_2012). Tumors for carriers of this variant showed MSH-H and loss of MLH1-PMS2 staining. The variant is absent from the large control datasets of ExAC and gnomAD (121282 and 246040, chrs tested respectively). The variant was identified in several affected individuals (Hendriks_2003; van Puijenbroek_2008; van der Klift_2016). Although several clinical diagnostic laboratories/reputable databases cite the variant with a classification of VUS, the collective evidence points towards a deleterious effect. Taken together, the variant was classified as VUS-Possibly Pathogenic, until more data becomes available.

#	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 15, 2024

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