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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 2, 2023
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:: RCV003995546.2

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:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004843299	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004843299

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 2, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004843299.1

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

Description

This missense variant replaces leucine with methionine at codon 741 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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