NM_000249.4(MLH1):c.244A>G (p.Thr82Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 16, 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:: RCV000166056.12

Allele description [Variation Report for NM_000249.4(MLH1):c.244A>G (p.Thr82Ala)]

NM_000249.4(MLH1):c.244A>G (p.Thr82Ala)

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.244A>G (p.Thr82Ala)

HGVS:

NC_000003.12:g.37000991A>G
NG_007109.2:g.12642A>G
NM_000249.4:c.244A>GMANE SELECT
NM_001167617.3:c.-46A>G
NM_001167618.3:c.-480A>G
NM_001167619.3:c.-388A>G
NM_001258271.2:c.244A>G
NM_001258273.2:c.-480A>G
NM_001258274.3:c.-480A>G
NM_001354615.2:c.-383A>G
NM_001354616.2:c.-388A>G
NM_001354617.2:c.-480A>G
NM_001354618.2:c.-480A>G
NM_001354619.2:c.-480A>G
NM_001354620.2:c.-46A>G
NM_001354621.2:c.-573A>G
NM_001354622.2:c.-686A>G
NM_001354623.2:c.-686A>G
NM_001354624.2:c.-583A>G
NM_001354625.2:c.-486A>G
NM_001354626.2:c.-583A>G
NM_001354627.2:c.-583A>G
NM_001354628.2:c.244A>G
NM_001354629.2:c.208-3410A>G
NM_001354630.2:c.244A>G
NP_000240.1:p.Thr82Ala
NP_000240.1:p.Thr82Ala
NP_001245200.1:p.Thr82Ala
NP_001341557.1:p.Thr82Ala
NP_001341559.1:p.Thr82Ala
LRG_216t1:c.244A>G
LRG_216:g.12642A>G
LRG_216p1:p.Thr82Ala
NC_000003.11:g.37042482A>G
NM_000249.3:c.244A>G
NM_001167617.1:c.-46A>G
p.T82A

Protein change:

T82A

Links:

dbSNP: rs587778998

NCBI 1000 Genomes Browser:

rs587778998

Molecular consequence:

NM_001167617.3:c.-46A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-388A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-383A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-388A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-480A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-46A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-573A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-686A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-686A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-583A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-486A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-583A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-583A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3410A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.244A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.244A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.244A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.244A>G - 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
SCV000216818	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 28, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19690142, 26300997 Citation Link,
SCV000908603	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21239990, 21404117, 22736432, 26300997, 31881334, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216818

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 28, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000908603

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 16, 2023)

germline

clinical testing

PubMed (6)
[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

Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases.

Mueller J, Gazzoli I, Bandipalliam P, Garber JE, Syngal S, Kolodner RD.

Cancer Res. 2009 Sep 1;69(17):7053-61. doi: 10.1158/0008-5472.CAN-09-0358. Epub 2009 Aug 18.

PubMed [citation]

PMID:: 19690142
PMCID:: PMC2761236

Integrated analysis of unclassified variants in mismatch repair genes.

Pastrello C, Pin E, Marroni F, Bedin C, Fornasarig M, Tibiletti MG, Oliani C, Ponz de Leon M, Urso ED, Della Puppa L, Agostini M, Viel A.

Genet Med. 2011 Feb;13(2):115-24. doi: 10.1097/GIM.0b013e3182011489.

PubMed [citation]

PMID:: 21239990

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000216818.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.T82A variant (also known as c.244A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 244. The threonine at codon 82 is replaced by alanine, an amino acid with similar properties. This variant has been identified in probands with HNPCC or HNPCC-related cancers and concordant tumors when available (Pastrello C et al. Genet Med. 2011 Feb;13(2):115-24,Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84, Borras E et al. Hum Mutat. 2012 Nov;33(11):1576-88, Simbolo M et al. Hered. Cancer Clin Pract. 2015 Aug 21;13(1), Ambry internal data). This variant is located in the ATPase functional domain and impaired MMR activity compared to wild-type (Borras E et al. Hum Mutat. 2012 Nov;33(11)). This paper also cites literature demonstrating alterations at the same codon, including p.T82K, p.T82M, and p.T82I, to be defective in MMR activity in yeast and/or human cells. This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

From Color Diagnostics, LLC DBA Color Health, SCV000908603.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces threonine with alanine at codon 82 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). Functional studies have shown that the mutant protein shows <10% of normal DNA-mismatch repair activity in vitro (PMID: 22736432, 31881334). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21239990, 26300997) and in individuals affected with colorectal cancer with tumors showing microsatellite instability (PMID: 21404117, 22736432). This variant has been identified in 2/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Thr82Ile, is known to be disease-causing, indicating the importance of threonine residue at this position for MLH1 function. Based on the available evidence, this variant is classified as 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 18, 2024

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