NM_000249.4(MLH1):c.2221C>A (p.Leu741Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 22, 2023
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:: RCV000166962.10

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Anterior segment dysgenesis 4
Anterior segment dysgenesis 4

MedGen
C1842031[conceptid] (1)
MedGen

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000217783	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000689868	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 6, 2022)	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

SCV000217783

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 22, 2023)

germline

clinical testing

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

Citation Link,

SCV000689868

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 6, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Development, technical validation, and clinical application of a multigene panel for hereditary gastrointestinal cancer and polyposis.

Ricci MT, Volorio S, Signoroni S, Mariani P, Mariette F, Sardella D, Pensotti V, Vitellaro M.

Tumori. 2019 Aug;105(4):338-352. doi: 10.1177/0300891619847085. Epub 2019 May 8.

PubMed [citation]

PMID:: 31068090

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 Ambry Genetics, SCV000217783.7

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

Description

The p.L741M variant (also known as c.2221C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide position 2221. The leucine at codon 741 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in a patient with ovarian cancer at age 46 and a family history of colorectal and other cancers (Ricci MT et al. Tumori, 2019 Aug;105:338-352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000689868.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine