NM_000249.4(MLH1):c.1676T>C (p.Leu559Pro) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Jun 18, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000522242.1

Allele description [Variation Report for NM_000249.4(MLH1):c.1676T>C (p.Leu559Pro)]

NM_000249.4(MLH1):c.1676T>C (p.Leu559Pro)

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.1676T>C (p.Leu559Pro)
HGVS:
  • NC_000003.12:g.37042276T>C
  • NG_007109.2:g.53927T>C
  • NM_000249.3:c.1676T>C
  • NM_000249.4:c.1676T>CMANE SELECT
  • NM_001167617.3:c.1382T>C
  • NM_001167618.3:c.953T>C
  • NM_001167619.3:c.953T>C
  • NM_001258271.2:c.1676T>C
  • NM_001258273.2:c.953T>C
  • NM_001258274.3:c.953T>C
  • NM_001354615.2:c.953T>C
  • NM_001354616.2:c.953T>C
  • NM_001354617.2:c.953T>C
  • NM_001354618.2:c.953T>C
  • NM_001354619.2:c.953T>C
  • NM_001354620.2:c.1382T>C
  • NM_001354621.2:c.653T>C
  • NM_001354622.2:c.653T>C
  • NM_001354623.2:c.653T>C
  • NM_001354624.2:c.602T>C
  • NM_001354625.2:c.602T>C
  • NM_001354626.2:c.602T>C
  • NM_001354627.2:c.602T>C
  • NM_001354628.2:c.1676T>C
  • NM_001354629.2:c.1577T>C
  • NM_001354630.2:c.1676T>C
  • NP_000240.1:p.Leu559Pro
  • NP_000240.1:p.Leu559Pro
  • NP_001161089.1:p.Leu461Pro
  • NP_001161090.1:p.Leu318Pro
  • NP_001161091.1:p.Leu318Pro
  • NP_001245200.1:p.Leu559Pro
  • NP_001245202.1:p.Leu318Pro
  • NP_001245203.1:p.Leu318Pro
  • NP_001341544.1:p.Leu318Pro
  • NP_001341545.1:p.Leu318Pro
  • NP_001341546.1:p.Leu318Pro
  • NP_001341547.1:p.Leu318Pro
  • NP_001341548.1:p.Leu318Pro
  • NP_001341549.1:p.Leu461Pro
  • NP_001341550.1:p.Leu218Pro
  • NP_001341551.1:p.Leu218Pro
  • NP_001341552.1:p.Leu218Pro
  • NP_001341553.1:p.Leu201Pro
  • NP_001341554.1:p.Leu201Pro
  • NP_001341555.1:p.Leu201Pro
  • NP_001341556.1:p.Leu201Pro
  • NP_001341557.1:p.Leu559Pro
  • NP_001341558.1:p.Leu526Pro
  • NP_001341559.1:p.Leu559Pro
  • LRG_216t1:c.1676T>C
  • LRG_216:g.53927T>C
  • LRG_216p1:p.Leu559Pro
  • NC_000003.11:g.37083767T>C
Protein change:
L201P
Links:
dbSNP: rs63750059
NCBI 1000 Genomes Browser:
rs63750059
Molecular consequence:
  • NM_000249.3:c.1676T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000249.4:c.1676T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1382T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1676T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1382T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1676T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1577T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1676T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000618313GeneDxcriteria provided, single submitter
Likely pathogenic
(Jun 18, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000618313.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted MLH1 c.1676T>C at the cDNA level, p.Leu559Pro (L559P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has been reported in an individual with MSI-H colon cancer from a family meeting Amsterdam II Lynch syndrome criteria (Hardt 2011). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) describes a family meeting Amsterdam I criteria and classifies this variant as likely pathogenic (Thompson 2014). MLH1 Leu559Pro was not observed in large population cohorts (Lek 2016). This variant is located in the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MLH1 Leu559Pro to be a likely pathogenic variant.

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

Last Updated: Oct 25, 2021

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