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NM_000249.4(MLH1):c.2221C>A (p.Leu741Met) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Feb 1, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000215072.9

Allele description [Variation Report for NM_000249.4(MLH1):c.2221C>A (p.Leu741Met)]

NM_000249.4(MLH1):c.2221C>A (p.Leu741Met)

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.2221C>A (p.Leu741Met)
HGVS:
  • NC_000003.12:g.37050603C>A
  • NG_007109.2:g.62254C>A
  • NM_000249.4:c.2221C>AMANE SELECT
  • NM_001167617.3:c.1927C>A
  • NM_001167618.3:c.1498C>A
  • NM_001167619.3:c.1498C>A
  • NM_001258271.2:c.2014C>A
  • NM_001258273.2:c.1498C>A
  • NM_001258274.3:c.1498C>A
  • NM_001354615.2:c.1498C>A
  • NM_001354616.2:c.1498C>A
  • NM_001354617.2:c.1498C>A
  • NM_001354618.2:c.1498C>A
  • NM_001354619.2:c.1498C>A
  • NM_001354620.2:c.1927C>A
  • NM_001354621.2:c.1198C>A
  • NM_001354622.2:c.1198C>A
  • NM_001354623.2:c.1198C>A
  • NM_001354624.2:c.1147C>A
  • NM_001354625.2:c.1147C>A
  • NM_001354626.2:c.1147C>A
  • NM_001354627.2:c.1147C>A
  • NM_001354628.2:c.2128C>A
  • NM_001354629.2:c.2122C>A
  • NM_001354630.2:c.2056C>A
  • NP_000240.1:p.Leu741Met
  • NP_000240.1:p.Leu741Met
  • NP_001161089.1:p.Leu643Met
  • NP_001161090.1:p.Leu500Met
  • NP_001161091.1:p.Leu500Met
  • NP_001245200.1:p.Leu672Met
  • NP_001245202.1:p.Leu500Met
  • NP_001245203.1:p.Leu500Met
  • NP_001341544.1:p.Leu500Met
  • NP_001341545.1:p.Leu500Met
  • NP_001341546.1:p.Leu500Met
  • NP_001341547.1:p.Leu500Met
  • NP_001341548.1:p.Leu500Met
  • NP_001341549.1:p.Leu643Met
  • NP_001341550.1:p.Leu400Met
  • NP_001341551.1:p.Leu400Met
  • NP_001341552.1:p.Leu400Met
  • NP_001341553.1:p.Leu383Met
  • NP_001341554.1:p.Leu383Met
  • NP_001341555.1:p.Leu383Met
  • NP_001341556.1:p.Leu383Met
  • NP_001341557.1:p.Leu710Met
  • NP_001341558.1:p.Leu708Met
  • NP_001341559.1:p.Leu686Met
  • LRG_216t1:c.2221C>A
  • LRG_216:g.62254C>A
  • LRG_216p1:p.Leu741Met
  • NC_000003.11:g.37092094C>A
  • NM_000249.3:c.2221C>A
  • p.L741M
Protein change:
L383M
Links:
dbSNP: rs786203583
NCBI 1000 Genomes Browser:
rs786203583
Molecular consequence:
  • NM_000249.4:c.2221C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1927C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.2014C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1498C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1927C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1198C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1198C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1198C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.1147C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.1147C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.1147C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.1147C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.2128C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.2122C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.2056C>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000279864GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Uncertain significance
(Feb 5, 2016) 		germlineclinical testing

Citation Link,

SCV004704362CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)		Uncertain significance
(Feb 1, 2024) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000279864.9

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

Description

This variant is denoted MLH1 c.2221C>A at the cDNA level, p.Leu741Met (L741M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu741Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu741Met occurs at a position that is conserved across species and is located within the Pms1p-interactive domain as well as the region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Leu741Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From CeGaT Center for Human Genetics Tuebingen, SCV004704362.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

MLH1: PM2

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Oct 20, 2024