NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 5, 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:: RCV001175812.6

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339534	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002714334	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10480359, 12655562, 16395668, 17510385, 20533529, 23403630, 23435383, 27499925, 30998989 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001339534

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 10, 2020)

germline

clinical testing

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

SCV002714334

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 5, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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

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

Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.

Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A.

Hum Genet. 1999 Jul-Aug;105(1-2):79-85.

PubMed [citation]

PMID:: 10480359

See all PubMed Citations (10)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001339534.2

#	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 alanine with aspartic acid at codon 586 in the PMS2/MLH3/PMS1 interacting domain of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a defect in MLH1 protein function (PMID: 30998989). This variant has been reported in a family affected with Lynch syndrome (PMID: 16395668) and has been reported to segregate with disease in multiple individuals from two families affected with Lynch syndrome (communication with an external laboratory; Clinvar variation ID: 89877). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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 Ambry Genetics, SCV002714334.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.A586D variant (also known as c.1757C>A), located in coding exon 16 of the MLH1 gene, results from a C to A substitution at nucleotide position 1757. The alanine at codon 586 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was identified in a family that met Amsterdam criteria for HNPCC/Lynch syndrome and one family member had a colorectal tumor that displayed loss of both MLH1/PMS2 on immunohistochemistry (Ambry internal data). In one study, this variant was detected in an HNPCC/Lynch family and was analyzed for aberrant splicing, which was not detected via RT-PCR analysis of mRNA isolated from the patient's lymphoblast cell cultures (Auclair et al. Hum Mutat. 2006; 27(2):145-154). Based on an internal structural assessment, p.A586D is moderately disruptive to the MLH1 C-terminal domain, inserting a large, charged side-chain into a hydrophobic pocket. Additionally, p.A586D is more disruptive than several nearby pathogenic variants (Gueneau E et al. Nat. Struct. Mol. Biol., 2013 Apr;20:461-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: Nov 10, 2024

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