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

Clinical significance:Uncertain significance (Last evaluated: Oct 20, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000781534.1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000919640Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Oct 20, 2017)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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