NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Jun 12, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000556108.1

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)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000625096Invitaecriteria provided, single submitter
Uncertain significance
(Jun 12, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000625096.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces leucine with phenylalanine at codon 582 of the MLH1 protein (p.Leu582Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with colon cancer (PMID: 18415027, 12547705), it has also been reported in an individual with Lynch syndrome (PMID: 27435373) as co-occurring with a variant in PMS2 (p.Glu504Gln) (PMID: 27435373), and it has been reported in an individual with gastrointestinal cancer (PMID: 23760103). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89870). Experimental studies have shown that this missense change results in loss of mismatch repair activity and loss of interaction with PMS2 (PMID: 20020535, 22753075). In summary, while this variant has been reported to impact on MLH1 function, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Dec 4, 2021

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