VCV001782872.5 - ClinVar

NM_000249.4(MLH1):c.193_201delinsC (p.Gly65fs)

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.

(4)

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/Likely pathogenic

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.193_201delinsC (p.Gly65fs)

Variation ID: 1782872 Accession: VCV001782872.5

Type and length

Indel, 9 bp

Location

Cytogenetic: 3p22.2 3: 36996695-36996703 (GRCh38) [ NCBI UCSC ] 3: 37038186-37038194 (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 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.193_201delinsC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Gly65fs	frameshift
NM_000249.3:c.193_201delinsC
NM_001167617.3:c.-97_-89delinsC		5 prime UTR
NM_001167618.3:c.-531_-523delinsC		5 prime UTR
NM_001167619.3:c.-439_-431delinsC		5 prime UTR
NM_001258271.2:c.193_201delinsC	NP_001245200.1:p.Gly65fs	frameshift
NM_001258273.2:c.-517+3032_-517+3040delinsC		intron variant
NM_001258274.3:c.-676_-668delinsC		5 prime UTR
NM_001354615.2:c.-434_-426delinsC		5 prime UTR
NM_001354616.2:c.-439_-431delinsC		5 prime UTR
NM_001354617.2:c.-531_-523delinsC		5 prime UTR
NM_001354618.2:c.-531_-523delinsC		5 prime UTR
NM_001354619.2:c.-531_-523delinsC		5 prime UTR
NM_001354620.2:c.-97_-89delinsC		5 prime UTR
NM_001354621.2:c.-624_-616delinsC		5 prime UTR
NM_001354622.2:c.-737_-729delinsC		5 prime UTR
NM_001354623.2:c.-723+2805_-723+2813delinsC		intron variant
NM_001354624.2:c.-634_-626delinsC		5 prime UTR
NM_001354625.2:c.-537_-529delinsC		5 prime UTR
NM_001354626.2:c.-634_-626delinsC		5 prime UTR
NM_001354627.2:c.-634_-626delinsC		5 prime UTR
NM_001354628.2:c.193_201delinsC	NP_001341557.1:p.Gly65fs	frameshift
NM_001354629.2:c.193_201delinsC	NP_001341558.1:p.Gly65fs	frameshift
NM_001354630.2:c.193_201delinsC	NP_001341559.1:p.Gly65fs	frameshift
NC_000003.12:g.36996695_36996703delinsC
NC_000003.11:g.37038186_37038194delinsC
NG_007109.2:g.8346_8354delinsC
NG_008418.1:g.1602_1610delinsG
LRG_216:g.8346_8354delinsC
LRG_216t1:c.193_201delGGCACCGGGinsC	LRG_216p1:p.Gly65Hisfs

... more HGVS ... less HGVS

Protein change

G65fs

Other names

Canonical SPDI

NC_000003.12:36996694:GGCACCGGG: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	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.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2017	RCV002410905.2
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 11, 2023	RCV003454304.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 18, 2023	RCV003476997.1

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.
Pathogenic (Jul 11, 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: SCV004186304.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Likely pathogenic (Oct 21, 2020)	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: SCV004193080.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (May 18, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220860.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: This variant alters the translational reading frame of the MLH1 mRNA and is predicted to cause the premature termination of MLH1 protein synthesis. To the … (more) This variant alters the translational reading frame of the MLH1 mRNA and is predicted to cause the premature termination of MLH1 protein synthesis. To the best of our knowledge, this variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. (less)
Pathogenic (Jan 06, 2017)	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: SCV002720742.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.193_201delGGCACCGGGinsC pathogenic mutation, located in coding exon 2 of the MLH1 gene, results from the deletion of 9 nucleotides and insertion of one nucleotide … (more) The c.193_201delGGCACCGGGinsC pathogenic mutation, located in coding exon 2 of the MLH1 gene, results from the deletion of 9 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G65Hfs*11). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

This variant alters the translational reading frame of the MLH1 mRNA and is predicted to cause the premature termination of MLH1 protein synthesis. To the best of our knowledge, this variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.

Comment:

The c.193_201delGGCACCGGGinsC pathogenic mutation, located in coding exon 2 of the MLH1 gene, results from the deletion of 9 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G65Hfs*11). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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.193_201delinsC (p.Gly65fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...