NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 12, 2022
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:: RCV000213700.9

Allele description [Variation Report for NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr)]

NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr)

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.2041G>A (p.Ala681Thr)

HGVS:

NC_000003.12:g.37048955G>A
NG_007109.2:g.60606G>A
NM_000249.4:c.2041G>AMANE SELECT
NM_001167617.3:c.1747G>A
NM_001167618.3:c.1318G>A
NM_001167619.3:c.1318G>A
NM_001258271.2:c.1896+1272G>A
NM_001258273.2:c.1318G>A
NM_001258274.3:c.1318G>A
NM_001354615.2:c.1318G>A
NM_001354616.2:c.1318G>A
NM_001354617.2:c.1318G>A
NM_001354618.2:c.1318G>A
NM_001354619.2:c.1318G>A
NM_001354620.2:c.1747G>A
NM_001354621.2:c.1018G>A
NM_001354622.2:c.1018G>A
NM_001354623.2:c.1018G>A
NM_001354624.2:c.967G>A
NM_001354625.2:c.967G>A
NM_001354626.2:c.967G>A
NM_001354627.2:c.967G>A
NM_001354628.2:c.1948G>A
NM_001354629.2:c.1942G>A
NM_001354630.2:c.1876G>A
NP_000240.1:p.Ala681Thr
NP_000240.1:p.Ala681Thr
NP_001161089.1:p.Ala583Thr
NP_001161090.1:p.Ala440Thr
NP_001161091.1:p.Ala440Thr
NP_001245202.1:p.Ala440Thr
NP_001245203.1:p.Ala440Thr
NP_001341544.1:p.Ala440Thr
NP_001341545.1:p.Ala440Thr
NP_001341546.1:p.Ala440Thr
NP_001341547.1:p.Ala440Thr
NP_001341548.1:p.Ala440Thr
NP_001341549.1:p.Ala583Thr
NP_001341550.1:p.Ala340Thr
NP_001341551.1:p.Ala340Thr
NP_001341552.1:p.Ala340Thr
NP_001341553.1:p.Ala323Thr
NP_001341554.1:p.Ala323Thr
NP_001341555.1:p.Ala323Thr
NP_001341556.1:p.Ala323Thr
NP_001341557.1:p.Ala650Thr
NP_001341558.1:p.Ala648Thr
NP_001341559.1:p.Ala626Thr
LRG_216t1:c.2041G>A
LRG_216:g.60606G>A
LRG_216p1:p.Ala681Thr
NC_000003.11:g.37090446G>A
NM_000249.3:c.2041G>A
P40692:p.Ala681Thr

Protein change:

A323T; ALA681THR

Links:

UniProtKB: P40692#VAR_004466; OMIM: 120436.0022; dbSNP: rs63750217

NCBI 1000 Genomes Browser:

rs63750217

Molecular consequence:

NM_001258271.2:c.1896+1272G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2041G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1747G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1747G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1018G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1018G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1018G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.967G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.967G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.967G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.967G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1948G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1942G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1876G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

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
SCV000275301	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Apr 12, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 11427529, 16083711, 16451135, 17510385, 18033691, 23403630, 24032978, 24362816, 28874130, 29596542, 29887214, 8880570, 9697702 Citation Link,
SCV000689855	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 22, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528707	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jul 7, 2021)	germline	curation	PubMed (12) [See all records that cite these PMIDs] 18033691, 28874130, 30093976, 32587781, 8880570, 21404117, 31386297, 10037723, 15864295, 16083711, 17510385, 29520894 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275301

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Apr 12, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link,

SCV000689855

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 22, 2020)

germline

clinical testing

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

SCV002528707

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jul 7, 2021)

germline

curation

PubMed (12)
[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	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

The interaction of DNA mismatch repair proteins with human exonuclease I.

Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R.

J Biol Chem. 2001 Aug 31;276(35):33011-8. Epub 2001 Jun 26.

PubMed [citation]

PMID:: 11427529

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

See all PubMed Citations (21)

Details of each submission

From Ambry Genetics, SCV000275301.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

The p.A681T pathogenic mutation (also known as c.2041G>A), located in coding exon 18 of the MLH1 gene, results from a G to A substitution at nucleotide position 2041. The alanine at codon 681 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple families either meeting Amsterdam II criteria or whose family history was suggestive of HNPCC/Lynch syndrome; it has also been shown to co-segregate with disease in several families (Froggatt NJ et al. J. Med. Genet. 1996 Sep;33:762-30; Shimodaira H et al. Nat. Genet. 1998 Aug;19:384-9; Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Dymerska D et al. 2014 Clin. Genet. 2014 Aug;86:190-3; Rossi BM et al. BMC Cancer. 2017 Sep;17:623). Tumor analysis of two related individuals who carried this alteration and were diagnosed with colorectal cancer under the age of 55 years showed high microsatellite instability (MSI-H) and loss of MLH1 on immunohistochemistry (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). In vitro studies have shown that while this alteration shows proficient MMR activity, it leads to decreased protein stability and thus, decreased protein expression (Raevaara TE et al. Gastroenterology. 2005 Aug;129:537-49; Takahashi M et al. Cancer Res. 2007 May;67:4595-604; Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41). Another functional analysis of this variant has demonstrated that this amino acid change causes a reduction in MLH1 and PMS2 binding and a >80% reduction in the interaction between MLH1 and hExo1, a member of a family of conserved exonucleases which are implicated in many DNA metabolic processes, including DNA mismatch repair (MMR) and recombination (Schmutte CJ et al. J. Biol. Chem. 2001 Aug;276:33011-8). This variant was identified as germline in a patient with MSI-H colon cancer demonstrating MLH1-/PMS2- and LOH (Hampel H et al. JAMA Oncol. 2018 Jun;4(6):806-813), and somatic data also supports pathogenicity (Shirts BH et al. Am. J. Hum. Genet. 2018 Jul;103(1):19-29). Furthermore, this alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation.

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

From Color Diagnostics, LLC DBA Color Health, SCV000689855.3

#	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 threonine at codon 681 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). Functional studies have shown that this variant results in reduced protein expression and stability (PMID: 21404117, 23403630, 25477341, 29520894, 32076465) and disrupts binding to PMS2, MRE11, and EXO1 (PMID: 10037723, 11427529, 12810663, 15864295, 21404117). This variant has been shown to eliminate the dominant negative mutator effect (PMID: 9697702, 17510385, 21404117) and decrease MMR activity (PMID: 17210669, 17510385). However, some studies have contradicted these results and shown near normal expression and activity of the mutant protein (PMID: 12810663, 16083711, 17510385, 21120944, 23403630, 30504929). This variant has been reported in more than 60 families (>70 individuals) affected with colorectal cancer that meet either Amsterdam or Bethesda criteria (PMID: 8880570, 16083711, 16451135, 17054581, 17505997, 18033691, 21404117, 21642682, 22736432, 23354017, 24032978, 28874130, 29596542, 30324682, 31386297, 31491536, 31660093). Most of these individuals had tumors with high microsatellite instability and undetectable MLH1 expression by immunohistochemistry (PMID: 16083711, 17054581, 18033691, 21120944, 22736432, 29596542). It has been reported that this variant segregates with disease in at least 7 families and is thought to be a founder mutation in the Polish population (PMID: 8880570, 16451135, 18033691). 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 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 Sema4, Sema4, SCV002528707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (12)

#	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: Mar 16, 2024

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