VCV001787138.2 - ClinVar

NM_000249.4(MLH1):c.2173del (p.Arg725fs)

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.

(1)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.2173del (p.Arg725fs)

Variation ID: 1787138 Accession: VCV001787138.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p22.2 3: 37050555 (GRCh38) [ NCBI UCSC ] 3: 37092046 (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	Jul 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.2173del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Arg725fs	frameshift
NM_001167617.3:c.1879del	NP_001161089.1:p.Arg627fs	frameshift
NM_001167618.3:c.1450del	NP_001161090.1:p.Arg484fs	frameshift
NM_001167619.3:c.1450del	NP_001161091.1:p.Arg484fs	frameshift
NM_001258271.2:c.1966del	NP_001245200.1:p.Arg656fs	frameshift
NM_001258273.2:c.1450del	NP_001245202.1:p.Arg484fs	frameshift
NM_001258274.3:c.1450del	NP_001245203.1:p.Arg484fs	frameshift
NM_001354615.2:c.1450del	NP_001341544.1:p.Arg484fs	frameshift
NM_001354616.2:c.1450del	NP_001341545.1:p.Arg484fs	frameshift
NM_001354617.2:c.1450del	NP_001341546.1:p.Arg484fs	frameshift
NM_001354618.2:c.1450del	NP_001341547.1:p.Arg484fs	frameshift
NM_001354619.2:c.1450del	NP_001341548.1:p.Arg484fs	frameshift
NM_001354620.2:c.1879del	NP_001341549.1:p.Arg627fs	frameshift
NM_001354621.2:c.1150del	NP_001341550.1:p.Arg384fs	frameshift
NM_001354622.2:c.1150del	NP_001341551.1:p.Arg384fs	frameshift
NM_001354623.2:c.1150del	NP_001341552.1:p.Arg384fs	frameshift
NM_001354624.2:c.1099del	NP_001341553.1:p.Arg367fs	frameshift
NM_001354625.2:c.1099del	NP_001341554.1:p.Arg367fs	frameshift
NM_001354626.2:c.1099del	NP_001341555.1:p.Arg367fs	frameshift
NM_001354627.2:c.1099del	NP_001341556.1:p.Arg367fs	frameshift
NM_001354628.2:c.2080del	NP_001341557.1:p.Arg694fs	frameshift
NM_001354629.2:c.2074del	NP_001341558.1:p.Arg692fs	frameshift
NM_001354630.2:c.2008del	NP_001341559.1:p.Arg670fs	frameshift
NC_000003.12:g.37050555del
NC_000003.11:g.37092046del
NG_007109.2:g.62206del
LRG_216:g.62206del
LRG_216t1:c.2173del	LRG_216p1:p.Arg725Alafs

... more HGVS ... less HGVS

Protein change

R627fs, R694fs, R384fs, R484fs, R367fs, R656fs, R670fs, R692fs, R725fs

Other names

Canonical SPDI

NC_000003.12:37050554:C:

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	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2022	RCV002432771.2

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.
Pathogenic (Jul 13, 2022)	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: SCV002726672.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.2173delC pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2173, causing … (more) The c.2173delC pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2173, causing a translational frameshift with a predicted alternate stop codon (p.R725ALS*58). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 25 amino acids. This frameshift impacts the last 32amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified as somatic in conjunction with MLH1 copy neutral loss of heterozygosity (CN-LOH) in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

The c.2173delC pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2173, causing a translational frameshift with a predicted alternate stop codon (p.R725ALS*58). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 25 amino acids. This frameshift impacts the last 32amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified as somatic in conjunction with MLH1 copy neutral loss of heterozygosity (CN-LOH) in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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 this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.2173del (p.Arg725fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...