VCV000582479.13 - ClinVar

NM_000249.4(MLH1):c.2164A>G (p.Lys722Glu)

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.

(3)

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.2164A>G (p.Lys722Glu)

Variation ID: 582479 Accession: VCV000582479.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37050546 (GRCh38) [ NCBI UCSC ] 3: 37092037 (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	May 1, 2024	Sep 26, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.2164A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Lys722Glu	missense
NM_001167617.3:c.1870A>G	NP_001161089.1:p.Lys624Glu	missense
NM_001167618.3:c.1441A>G	NP_001161090.1:p.Lys481Glu	missense
NM_001167619.3:c.1441A>G	NP_001161091.1:p.Lys481Glu	missense
NM_001258271.2:c.1957A>G	NP_001245200.1:p.Lys653Glu	missense
NM_001258273.2:c.1441A>G	NP_001245202.1:p.Lys481Glu	missense
NM_001258274.3:c.1441A>G	NP_001245203.1:p.Lys481Glu	missense
NM_001354615.2:c.1441A>G	NP_001341544.1:p.Lys481Glu	missense
NM_001354616.2:c.1441A>G	NP_001341545.1:p.Lys481Glu	missense
NM_001354617.2:c.1441A>G	NP_001341546.1:p.Lys481Glu	missense
NM_001354618.2:c.1441A>G	NP_001341547.1:p.Lys481Glu	missense
NM_001354619.2:c.1441A>G	NP_001341548.1:p.Lys481Glu	missense
NM_001354620.2:c.1870A>G	NP_001341549.1:p.Lys624Glu	missense
NM_001354621.2:c.1141A>G	NP_001341550.1:p.Lys381Glu	missense
NM_001354622.2:c.1141A>G	NP_001341551.1:p.Lys381Glu	missense
NM_001354623.2:c.1141A>G	NP_001341552.1:p.Lys381Glu	missense
NM_001354624.2:c.1090A>G	NP_001341553.1:p.Lys364Glu	missense
NM_001354625.2:c.1090A>G	NP_001341554.1:p.Lys364Glu	missense
NM_001354626.2:c.1090A>G	NP_001341555.1:p.Lys364Glu	missense
NM_001354627.2:c.1090A>G	NP_001341556.1:p.Lys364Glu	missense
NM_001354628.2:c.2071A>G	NP_001341557.1:p.Lys691Glu	missense
NM_001354629.2:c.2065A>G	NP_001341558.1:p.Lys689Glu	missense
NM_001354630.2:c.1999A>G	NP_001341559.1:p.Lys667Glu	missense
NC_000003.12:g.37050546A>G
NC_000003.11:g.37092037A>G
NG_007109.2:g.62197A>G
LRG_216:g.62197A>G
LRG_216t1:c.2164A>G	LRG_216p1:p.Lys722Glu

... more HGVS ... less HGVS

Protein change

K722E, K481E, K667E, K381E, K653E, K689E, K364E, K624E, K691E

Other names

Canonical SPDI

NC_000003.12:37050545: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

dbSNP: rs750596783 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	5691	5752

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 nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Sep 3, 2022	RCV000706561.5
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 26, 2022	RCV001014654.7

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 (Sep 03, 2022)	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: SCV000835618.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: 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 … (more) 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. 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. ClinVar contains an entry for this variant (Variation ID: 582479). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs750596783, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 722 of the MLH1 protein (p.Lys722Glu). (less)
Uncertain significance (Sep 26, 2022)	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: SCV001346836.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces lysine with glutamic acid at codon 722 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact … (more) This missense variant replaces lysine with glutamic acid at codon 722 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). 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 1/251162 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 (Jan 22, 2019)	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: SCV001175388.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.K722E variant (also known as c.2164A>G), located in coding exon 19 of the MLH1 gene, results from an A to G substitution at nucleotide … (more) The p.K722E variant (also known as c.2164A>G), located in coding exon 19 of the MLH1 gene, results from an A to G substitution at nucleotide position 2164. The lysine at codon 722 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

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. 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. ClinVar contains an entry for this variant (Variation ID: 582479). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs750596783, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 722 of the MLH1 protein (p.Lys722Glu).

Comment:

This missense variant replaces lysine with glutamic acid at codon 722 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). 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 1/251162 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.K722E variant (also known as c.2164A>G), located in coding exon 19 of the MLH1 gene, results from an A to G substitution at nucleotide position 2164. The lysine at codon 722 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). 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 rs750596783 ...

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.2164A>G (p.Lys722Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750596783 ...