VCV000142946.28 - ClinVar

NM_000249.4(MLH1):c.1489C>T (p.Arg497Trp)

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.

(9)

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(7); Likely 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.1489C>T (p.Arg497Trp)

Variation ID: 142946 Accession: VCV000142946.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37028863 (GRCh38) [ NCBI UCSC ] 3: 37070354 (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	Apr 29, 2017	Dec 14, 2024	May 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1489C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Arg497Trp	missense
NM_001167617.3:c.1195C>T	NP_001161089.1:p.Arg399Trp	missense
NM_001167618.3:c.766C>T	NP_001161090.1:p.Arg256Trp	missense
NM_001167619.3:c.766C>T	NP_001161091.1:p.Arg256Trp	missense
NM_001258271.2:c.1489C>T	NP_001245200.1:p.Arg497Trp	missense
NM_001258273.2:c.766C>T	NP_001245202.1:p.Arg256Trp	missense
NM_001258274.3:c.766C>T	NP_001245203.1:p.Arg256Trp	missense
NM_001354615.2:c.766C>T	NP_001341544.1:p.Arg256Trp	missense
NM_001354616.2:c.766C>T	NP_001341545.1:p.Arg256Trp	missense
NM_001354617.2:c.766C>T	NP_001341546.1:p.Arg256Trp	missense
NM_001354618.2:c.766C>T	NP_001341547.1:p.Arg256Trp	missense
NM_001354619.2:c.766C>T	NP_001341548.1:p.Arg256Trp	missense
NM_001354620.2:c.1195C>T	NP_001341549.1:p.Arg399Trp	missense
NM_001354621.2:c.466C>T	NP_001341550.1:p.Arg156Trp	missense
NM_001354622.2:c.466C>T	NP_001341551.1:p.Arg156Trp	missense
NM_001354623.2:c.466C>T	NP_001341552.1:p.Arg156Trp	missense
NM_001354624.2:c.415C>T	NP_001341553.1:p.Arg139Trp	missense
NM_001354625.2:c.415C>T	NP_001341554.1:p.Arg139Trp	missense
NM_001354626.2:c.415C>T	NP_001341555.1:p.Arg139Trp	missense
NM_001354627.2:c.415C>T	NP_001341556.1:p.Arg139Trp	missense
NM_001354628.2:c.1489C>T	NP_001341557.1:p.Arg497Trp	missense
NM_001354629.2:c.1390C>T	NP_001341558.1:p.Arg464Trp	missense
NM_001354630.2:c.1489C>T	NP_001341559.1:p.Arg497Trp	missense
NC_000003.12:g.37028863C>T
NC_000003.11:g.37070354C>T
NG_007109.2:g.40514C>T
LRG_216:g.40514C>T
LRG_216t1:c.1489C>T	LRG_216p1:p.Arg497Trp

... more HGVS ... less HGVS

Protein change

R497W, R139W, R156W, R256W, R399W, R464W

Other names

Canonical SPDI

NC_000003.12:37028862: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.

0.00020 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00005

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA005559 dbSNP: rs200830026 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	5768	5829

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 (3)	criteria provided, multiple submitters, no conflicts	May 10, 2024	RCV000132432.16
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 11, 2017	RCV000588886.2
Colorectal cancer, hereditary nonpolyposis, type 2 Mismatch repair cancer syndrome 1	not provided (1)	no classification provided	-	RCV001535466.2
Hereditary nonpolyposis colorectal neoplasms	Likely benign (1)	criteria provided, single submitter	Dec 12, 2023	RCV000168002.13
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 24, 2024	RCV003998147.3
Colorectal cancer, hereditary nonpolyposis, type 2	Uncertain significance (1)	criteria provided, single submitter	Dec 14, 2023	RCV004567155.1

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.
Uncertain significance (Nov 01, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696114.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due … (more) Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121412 (1/40469), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." (less)
Uncertain significance (Jan 11, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000569883.3 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to … (more) This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg497Trp was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg497Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PMS2/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg497Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
Likely benign (Dec 12, 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: SCV000218653.11 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Dec 14, 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: SCV005058018.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (May 10, 2024)	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: SCV000187526.8 First in ClinVar: Aug 06, 2014 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 32832836 Comment: The p.R497W variant (also known as c.1489C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide … (more) The p.R497W variant (also known as c.1489C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1489. The arginine at codon 497 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
Uncertain significance (Nov 18, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528656.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: To the best of our knowledge, the MLH1 c.1489C>T (p.R497W) variant has not been reported in individuals with MLH1-related diseases. It was observed in 6/24970 … (more) To the best of our knowledge, the MLH1 c.1489C>T (p.R497W) variant has not been reported in individuals with MLH1-related diseases. It was observed in 6/24970 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 142946). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
Uncertain significance (Feb 17, 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: SCV000684750.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces arginine with tryptophan at codon 497 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 9/282892 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)
Uncertain Significance (Mar 24, 2024)	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: SCV004841024.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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 arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact … (more) This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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: 6 Zygosity: Single Heterozygote
not provided (-)	no classification provided Method: phenotyping only	Colorectal cancer, hereditary nonpolyposis, type 2 Turcot syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749387.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant interpreted as Uncertain significance and reported on 10-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 10-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Anus neoplasm (present) , Family history of cancer (present) Indication for testing: Presymptomatic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2018-10-30 Testing laboratory interpretation: Uncertain significance

Comment:

Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121412 (1/40469), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

Comment:

This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg497Trp was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg497Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PMS2/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg497Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Comment:

The p.R497W variant (also known as c.1489C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1489. The arginine at codon 497 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Comment:

This missense variant replaces arginine with tryptophan at codon 497 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 9/282892 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:

This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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:

Variant interpreted as Uncertain significance and reported on 10-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836

Text-mined citations for rs200830026 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.1489C>T (p.Arg497Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200830026 ...