VCV001740901.6 - ClinVar

NM_000249.4(MLH1):c.447G>T (p.Gln149His)

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.

(2)

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.447G>T (p.Gln149His)

Variation ID: 1740901 Accession: VCV001740901.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37007057 (GRCh38) [ NCBI UCSC ] 3: 37048548 (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	Nov 29, 2022	May 1, 2024	May 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.447G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Gln149His	missense
NM_001167617.3:c.153G>T	NP_001161089.1:p.Gln51His	missense
NM_001167618.3:c.-277G>T		5 prime UTR
NM_001167619.3:c.-185G>T		5 prime UTR
NM_001258271.2:c.447G>T	NP_001245200.1:p.Gln149His	missense
NM_001258273.2:c.-277G>T		5 prime UTR
NM_001258274.3:c.-277G>T		5 prime UTR
NM_001354615.2:c.-185G>T		5 prime UTR
NM_001354616.2:c.-185G>T		5 prime UTR
NM_001354617.2:c.-277G>T		5 prime UTR
NM_001354618.2:c.-277G>T		5 prime UTR
NM_001354619.2:c.-277G>T		5 prime UTR
NM_001354620.2:c.153G>T	NP_001341549.1:p.Gln51His	missense
NM_001354621.2:c.-370G>T		5 prime UTR
NM_001354622.2:c.-483G>T		5 prime UTR
NM_001354623.2:c.-483G>T		5 prime UTR
NM_001354624.2:c.-380G>T		5 prime UTR
NM_001354625.2:c.-288G>T		5 prime UTR
NM_001354626.2:c.-380G>T		5 prime UTR
NM_001354627.2:c.-380G>T		5 prime UTR
NM_001354628.2:c.447G>T	NP_001341557.1:p.Gln149His	missense
NM_001354629.2:c.348G>T	NP_001341558.1:p.Gln116His	missense
NM_001354630.2:c.447G>T	NP_001341559.1:p.Gln149His	missense
NC_000003.12:g.37007057G>T
NC_000003.11:g.37048548G>T
NG_007109.2:g.18708G>T
LRG_216:g.18708G>T
LRG_216t1:c.447G>T	LRG_216p1:p.Gln149His

... more HGVS ... less HGVS

Protein change

Q149H, Q51H, Q116H

Other names

Canonical SPDI

NC_000003.12:37007056:G: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.

Links

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 cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	May 16, 2023	RCV002328552.3
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Feb 28, 2022	RCV003102593.3

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 (May 16, 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: SCV002637478.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 17440950 Comment: The p.Q149H variant (also known as c.447G>T), located in coding exon 5 of the MLH1 gene, results from a G to T substitution at nucleotide … (more) The p.Q149H variant (also known as c.447G>T), located in coding exon 5 of the MLH1 gene, results from a G to T substitution at nucleotide position 447. The glutamine at codon 149 is replaced by histidine, an amino acid with highly similar properties. The same alteration due to a different nucleotide substitution (c.447G>C) was detected in an individual with metachronous colon cancers first diagnosed at age 34; the tumor demonstrated loss of MLH1 by IHC and absent MLH1 promoter hypermethylation (Ewald J et al. Br J Surg. 2007 Aug;94:1020-7). 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)
Uncertain significance (Feb 28, 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: SCV003321668.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Comment: This variant has not been reported in the literature in individuals affected with MLH1-related conditions. In summary, the available evidence is currently insufficient to determine … (more) This variant has not been reported in the literature in individuals affected with MLH1-related conditions. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 149 of the MLH1 protein (p.Gln149His). (less)

Comment:

The p.Q149H variant (also known as c.447G>T), located in coding exon 5 of the MLH1 gene, results from a G to T substitution at nucleotide position 447. The glutamine at codon 149 is replaced by histidine, an amino acid with highly similar properties. The same alteration due to a different nucleotide substitution (c.447G>C) was detected in an individual with metachronous colon cancers first diagnosed at age 34; the tumor demonstrated loss of MLH1 by IHC and absent MLH1 promoter hypermethylation (Ewald J et al. Br J Surg. 2007 Aug;94:1020-7). 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.

Comment:

This variant has not been reported in the literature in individuals affected with MLH1-related conditions. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 149 of the MLH1 protein (p.Gln149His).

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
Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer.	Ewald J	The British journal of surgery	2007	PMID: 17440950

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.447G>T (p.Gln149His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...