NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 8, 2022
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:: RCV000524249.6

Allele description [Variation Report for NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp)]

NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp)

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.1757C>A (p.Ala586Asp)

HGVS:

NC_000003.12:g.37047544C>A
NG_007109.2:g.59195C>A
NM_000249.4:c.1757C>AMANE SELECT
NM_001167617.3:c.1463C>A
NM_001167618.3:c.1034C>A
NM_001167619.3:c.1034C>A
NM_001258271.2:c.1757C>A
NM_001258273.2:c.1034C>A
NM_001258274.3:c.1034C>A
NM_001354615.2:c.1034C>A
NM_001354616.2:c.1034C>A
NM_001354617.2:c.1034C>A
NM_001354618.2:c.1034C>A
NM_001354619.2:c.1034C>A
NM_001354620.2:c.1463C>A
NM_001354621.2:c.734C>A
NM_001354622.2:c.734C>A
NM_001354623.2:c.734C>A
NM_001354624.2:c.683C>A
NM_001354625.2:c.683C>A
NM_001354626.2:c.683C>A
NM_001354627.2:c.683C>A
NM_001354628.2:c.1757C>A
NM_001354629.2:c.1658C>A
NM_001354630.2:c.1732-973C>A
NP_000240.1:p.Ala586Asp
NP_000240.1:p.Ala586Asp
NP_001161089.1:p.Ala488Asp
NP_001161090.1:p.Ala345Asp
NP_001161091.1:p.Ala345Asp
NP_001245200.1:p.Ala586Asp
NP_001245202.1:p.Ala345Asp
NP_001245203.1:p.Ala345Asp
NP_001341544.1:p.Ala345Asp
NP_001341545.1:p.Ala345Asp
NP_001341546.1:p.Ala345Asp
NP_001341547.1:p.Ala345Asp
NP_001341548.1:p.Ala345Asp
NP_001341549.1:p.Ala488Asp
NP_001341550.1:p.Ala245Asp
NP_001341551.1:p.Ala245Asp
NP_001341552.1:p.Ala245Asp
NP_001341553.1:p.Ala228Asp
NP_001341554.1:p.Ala228Asp
NP_001341555.1:p.Ala228Asp
NP_001341556.1:p.Ala228Asp
NP_001341557.1:p.Ala586Asp
NP_001341558.1:p.Ala553Asp
LRG_216t1:c.1757C>A
LRG_216:g.59195C>A
LRG_216p1:p.Ala586Asp
NC_000003.11:g.37089035C>A
NM_000249.3:c.1757C>A

Protein change:

A228D

Links:

dbSNP: rs63750587

NCBI 1000 Genomes Browser:

rs63750587

Molecular consequence:

NM_001354630.2:c.1732-973C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1463C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1463C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1658C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284033	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30998989, 16395668, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284033

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.

Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, Duval A, Coulet F, Muleris M.

Gastroenterology. 2019 Aug;157(2):421-431. doi: 10.1053/j.gastro.2019.03.071. Epub 2019 Apr 15.

PubMed [citation]

PMID:: 30998989

Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]

PMID:: 16395668

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000284033.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 30998989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 89877). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 16395668; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 586 of the MLH1 protein (p.Ala586Asp).

#	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: Jul 23, 2024

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