NM_000249.4(MLH1):c.125C>T (p.Ala42Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 19, 2024
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:: RCV000115455.16

Allele description [Variation Report for NM_000249.4(MLH1):c.125C>T (p.Ala42Val)]

NM_000249.4(MLH1):c.125C>T (p.Ala42Val)

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.125C>T (p.Ala42Val)

Other names:

p.A42V:GCA>GTA

HGVS:

NC_000003.12:g.36996627C>T
NG_007109.2:g.8278C>T
NG_008418.1:g.1678G>A
NM_000249.4:c.125C>TMANE SELECT
NM_001167617.3:c.-165C>T
NM_001167618.3:c.-599C>T
NM_001167619.3:c.-507C>T
NM_001258271.2:c.125C>T
NM_001258273.2:c.-517+2964C>T
NM_001258274.3:c.-744C>T
NM_001354615.2:c.-502C>T
NM_001354616.2:c.-507C>T
NM_001354617.2:c.-599C>T
NM_001354618.2:c.-599C>T
NM_001354619.2:c.-599C>T
NM_001354620.2:c.-165C>T
NM_001354621.2:c.-692C>T
NM_001354622.2:c.-805C>T
NM_001354623.2:c.-723+2737C>T
NM_001354624.2:c.-702C>T
NM_001354625.2:c.-605C>T
NM_001354626.2:c.-702C>T
NM_001354627.2:c.-702C>T
NM_001354628.2:c.125C>T
NM_001354629.2:c.125C>T
NM_001354630.2:c.125C>T
NP_000240.1:p.Ala42Val
NP_000240.1:p.Ala42Val
NP_001245200.1:p.Ala42Val
NP_001341557.1:p.Ala42Val
NP_001341558.1:p.Ala42Val
NP_001341559.1:p.Ala42Val
LRG_216t1:c.125C>T
LRG_216:g.8278C>T
LRG_216p1:p.Ala42Val
NC_000003.11:g.37038118C>T
NM_000249.3:c.125C>T
p.A42V

Protein change:

A42V

Links:

dbSNP: rs587778901

NCBI 1000 Genomes Browser:

rs587778901

Molecular consequence:

NM_001167617.3:c.-165C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-599C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-507C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-744C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-502C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-507C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-599C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-599C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-599C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-165C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-692C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-805C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-702C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-605C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-702C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-702C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2737C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.125C>T - 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
SCV000216707	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15475387, 22006311 Citation Link,
SCV000684733	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 11, 2020)	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

SCV000216707

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 19, 2024)

germline

clinical testing

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

Citation Link,

SCV000684733

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 11, 2020)

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

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.

Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King MC, Swisher EM.

Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. doi: 10.1073/pnas.1115052108. Epub 2011 Oct 17.

PubMed [citation]

PMID:: 22006311
PMCID:: PMC3207658

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000216707.9

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

Description

The p.A42V variant (also known as c.125C>T), located in coding exon 2 of the MLH1 gene, results from a C to T substitution at nucleotide position 125. The alanine at codon 42 is replaced by valine, an amino acid with similar properties. The p.A42V alteration has been shown to have greater than 67% reduced mismatch repair function in yeast (Ellison AR et al. Nucleic Acids Res. 2004 Oct;32(18):5321-38). However, this alteration was reported in an individual with normal microsatellite stability and immunohistochemistry studies and interpreted to be benign (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7). This variant has also been identified in probands whose Lynch syndrome-associated tumors demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data). 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, SCV000684733.4

#	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 alanine with valine at codon 42 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 found that a hybrid human-yeast version of this variant protein produces a high mutator phenotype (PMID: 15475387), however, the clinical significance of this functional finding is uncertain. This variant has been reported in an individual affected with ovarian cancer whose tumor showed low microsatellite instability and the presence of MLH1 protein by immunohistochemistry (PMID: 22006311; InSiGHT database). This variant has been identified in 1/251434 chromosomes 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: Sep 29, 2024

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