VCV000134657.13 - ClinVar

NM_000249.4(MLH1):c.721A>G (p.Lys241Glu)

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.

(7)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.721A>G (p.Lys241Glu)

Variation ID: 134657 Accession: VCV000134657.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37014475 (GRCh38) [ NCBI UCSC ] 3: 37055966 (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	Jun 9, 2014	Aug 11, 2024	Jun 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.721A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Lys241Glu	missense
NM_001167617.3:c.427A>G	NP_001161089.1:p.Lys143Glu	missense
NM_001167618.3:c.-3A>G		5 prime UTR
NM_001167619.3:c.-3A>G		5 prime UTR
NM_001258271.2:c.721A>G	NP_001245200.1:p.Lys241Glu	missense
NM_001258273.2:c.-3A>G		5 prime UTR
NM_001258274.3:c.-3A>G		5 prime UTR
NM_001354615.2:c.-3A>G		5 prime UTR
NM_001354616.2:c.-3A>G		5 prime UTR
NM_001354617.2:c.-3A>G		5 prime UTR
NM_001354618.2:c.-3A>G		5 prime UTR
NM_001354619.2:c.-3A>G		5 prime UTR
NM_001354620.2:c.427A>G	NP_001341549.1:p.Lys143Glu	missense
NM_001354621.2:c.-140+2376A>G		intron variant
NM_001354622.2:c.-209A>G		5 prime UTR
NM_001354623.2:c.-209A>G		5 prime UTR
NM_001354624.2:c.-106A>G		5 prime UTR
NM_001354625.2:c.-106A>G		5 prime UTR
NM_001354626.2:c.-106A>G		5 prime UTR
NM_001354627.2:c.-106A>G		5 prime UTR
NM_001354628.2:c.721A>G	NP_001341557.1:p.Lys241Glu	missense
NM_001354629.2:c.622A>G	NP_001341558.1:p.Lys208Glu	missense
NM_001354630.2:c.721A>G	NP_001341559.1:p.Lys241Glu	missense
NC_000003.12:g.37014475A>G
NC_000003.11:g.37055966A>G
NG_007109.2:g.26126A>G
LRG_216:g.26126A>G
LRG_216t1:c.721A>G	LRG_216p1:p.Lys241Glu

... more HGVS ... less HGVS

Protein change

K241E, K208E, K143E

Other names

Canonical SPDI

NC_000003.12:37014474:A:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA011796 dbSNP: rs587778447 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.
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000121358.3
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 3, 2024	RCV000571271.4
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2022	RCV000767137.3
Colorectal cancer, hereditary nonpolyposis, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 14, 2023	RCV000662556.2
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Jan 11, 2024	RCV000694594.4
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2023	RCV003997345.2

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.
Uncertain significance (Jul 01, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000572582.5 First in ClinVar: Jun 09, 2014 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 22753075) (less)
Uncertain significance (Mar 14, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018155.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (May 12, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785146.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018
Uncertain significance (Jan 11, 2024)	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: SCV000823045.3 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 241 of the MLH1 protein … (more) This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 241 of the MLH1 protein (p.Lys241Glu). This variant is not present in population databases (gnomAD no frequency). 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: 134657). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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: SCV004840899.1 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 lysine with glutamic acid at codon 241 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant … (more) This missense variant replaces lysine with glutamic acid at codon 241 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 not been identified 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: 2
Uncertain significance (Jun 03, 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: SCV000662060.6 First in ClinVar: Jan 01, 2018 Last updated: Aug 11, 2024	Comment: The p.K241E variant (also known as c.721A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide … (more) The p.K241E variant (also known as c.721A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 721. The lysine at codon 241 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well 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. (less)
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085538.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 22753075)

Comment:

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 241 of the MLH1 protein (p.Lys241Glu). This variant is not present in population databases (gnomAD no frequency). 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: 134657). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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 lysine with glutamic acid at codon 241 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 not been identified 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.K241E variant (also known as c.721A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 721. The lysine at codon 241 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well 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.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs587778447 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.721A>G (p.Lys241Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778447 ...