VCV000186027.36 - ClinVar

NM_000249.4(MLH1):c.452C>T (p.Thr151Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(9); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.452C>T (p.Thr151Met)

Variation ID: 186027 Accession: VCV000186027.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37007062 (GRCh38) [ NCBI UCSC ] 3: 37048553 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 10, 2018	Oct 20, 2024	Dec 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.452C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Thr151Met	missense
NM_001167617.3:c.158C>T	NP_001161089.1:p.Thr53Met	missense
NM_001167618.3:c.-272C>T		5 prime UTR
NM_001167619.3:c.-180C>T		5 prime UTR
NM_001258271.2:c.452C>T	NP_001245200.1:p.Thr151Met	missense
NM_001258273.2:c.-272C>T		5 prime UTR
NM_001258274.3:c.-272C>T		5 prime UTR
NM_001354615.2:c.-180C>T		5 prime UTR
NM_001354616.2:c.-180C>T		5 prime UTR
NM_001354617.2:c.-272C>T		5 prime UTR
NM_001354618.2:c.-272C>T		5 prime UTR
NM_001354619.2:c.-272C>T		5 prime UTR
NM_001354620.2:c.158C>T	NP_001341549.1:p.Thr53Met	missense
NM_001354621.2:c.-365C>T		5 prime UTR
NM_001354622.2:c.-478C>T		5 prime UTR
NM_001354623.2:c.-478C>T		5 prime UTR
NM_001354624.2:c.-375C>T		5 prime UTR
NM_001354625.2:c.-283C>T		5 prime UTR
NM_001354626.2:c.-375C>T		5 prime UTR
NM_001354627.2:c.-375C>T		5 prime UTR
NM_001354628.2:c.452C>T	NP_001341557.1:p.Thr151Met	missense
NM_001354629.2:c.353C>T	NP_001341558.1:p.Thr118Met	missense
NM_001354630.2:c.452C>T	NP_001341559.1:p.Thr151Met	missense
NC_000003.12:g.37007062C>T
NC_000003.11:g.37048553C>T
NG_007109.2:g.18713C>T
LRG_216:g.18713C>T
LRG_216t1:c.452C>T	LRG_216p1:p.Thr151Met

... more HGVS ... less HGVS

Protein change

T151M, T53M, T118M

Other names

Canonical SPDI

NC_000003.12:37007061:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA010475 dbSNP: rs776969475 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MLH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5694	5755

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 7, 2023	RCV000165547.11
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Dec 24, 2023	RCV000473875.9
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Aug 7, 2023	RCV001569830.16
MLH1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 13, 2023	RCV003398846.4
Colorectal cancer, hereditary nonpolyposis, type 2	Uncertain significance (1)	criteria provided, single submitter	Oct 3, 2023	RCV003462179.1
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2023	RCV003995426.2
Ovarian cancer	Benign (1)	criteria provided, single submitter	Jan 1, 2022	RCV003153446.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ovarian cancer Affected status: yes Allele origin: germline	Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University Accession: SCV003843309.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023
Uncertain significance (Aug 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001793986.2 First in ClinVar: Aug 21, 2021 Last updated: Aug 18, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 30122538) (less)
Uncertain significance (Oct 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195082.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Nov 09, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220889.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 33471991‚ 32658311 Comment: The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021) and colorectal cancer (PMID: 32658311 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Dec 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000543661.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 151 of the MLH1 protein (p.Thr151Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 151 of the MLH1 protein (p.Thr151Met). This variant is present in population databases (rs776969475, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186027). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004835287.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251398 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. (less) Number of individuals with the variant: 4
Uncertain significance (Aug 07, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000216279.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The p.T151M variant (also known as c.452C>T), located in coding exon 5 of the MLH1 gene, results from a C to T substitution at nucleotide … (more) The p.T151M variant (also known as c.452C>T), located in coding exon 5 of the MLH1 gene, results from a C to T substitution at nucleotide position 452. The threonine at codon 151 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004149360.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Jul 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MLH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105403.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MLH1 c.452C>T variant is predicted to result in the amino acid substitution p.Thr151Met. To our knowledge, this variant has not been reported in the … (more) The MLH1 c.452C>T variant is predicted to result in the amino acid substitution p.Thr151Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37048553-C-T). It has conflicting interpretations of benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186027/), At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Apr 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000911260.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Comment: This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 4/251398 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. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 30122538)

Comment:

The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021) and colorectal cancer (PMID: 32658311 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 151 of the MLH1 protein (p.Thr151Met). This variant is present in population databases (rs776969475, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186027). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251398 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.

Comment:

The p.T151M variant (also known as c.452C>T), located in coding exon 5 of the MLH1 gene, results from a C to T substitution at nucleotide position 452. The threonine at codon 151 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The MLH1 c.452C>T variant is predicted to result in the amino acid substitution p.Thr151Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37048553-C-T). It has conflicting interpretations of benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186027/), At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 4/251398 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This missense variant replaces threonine with methionine at codon 151 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 4/251398 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.	Akcay IM	International journal of cancer	2021	PMID: 32658311

Text-mined citations for rs776969475 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.452C>T (p.Thr151Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs776969475 ...