VCV002674504.3 - ClinVar

NM_000249.4(MLH1):c.1667+2T>G

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.

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.1667+2T>G

Variation ID: 2674504 Accession: VCV002674504.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37040296 (GRCh38) [ NCBI UCSC ] 3: 37081787 (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	Dec 25, 2023	Aug 11, 2024	Apr 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1667+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000249.3:c.1667+2T>G
NM_001167617.3:c.1373+2T>G		splice donor
NM_001167618.3:c.944+2T>G		splice donor
NM_001167619.3:c.944+2T>G		splice donor
NM_001258271.2:c.1667+2T>G		splice donor
NM_001258273.2:c.944+2T>G		splice donor
NM_001258274.3:c.944+2T>G		splice donor
NM_001354615.2:c.944+2T>G		splice donor
NM_001354616.2:c.944+2T>G		splice donor
NM_001354617.2:c.944+2T>G		splice donor
NM_001354618.2:c.944+2T>G		splice donor
NM_001354619.2:c.944+2T>G		splice donor
NM_001354620.2:c.1373+2T>G		splice donor
NM_001354621.2:c.644+2T>G		splice donor
NM_001354622.2:c.644+2T>G		splice donor
NM_001354623.2:c.644+2T>G		splice donor
NM_001354624.2:c.593+2T>G		splice donor
NM_001354625.2:c.593+2T>G		splice donor
NM_001354626.2:c.593+2T>G		splice donor
NM_001354627.2:c.593+2T>G		splice donor
NM_001354628.2:c.1667+2T>G		splice donor
NM_001354629.2:c.1568+2T>G		splice donor
NM_001354630.2:c.1667+2T>G		splice donor
NC_000003.12:g.37040296T>G
NC_000003.11:g.37081787T>G
NG_007109.2:g.51947T>G
LRG_216:g.51947T>G
LRG_216t1:c.1667+2T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:37040295:T: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.

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.
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (1)	criteria provided, single submitter	Jul 21, 2023	RCV003452699.1
Hereditary nonpolyposis colorectal neoplasms	Likely pathogenic (1)	criteria provided, single submitter	Jun 11, 2023	RCV003594684.2
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2024	RCV004634266.1

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 21, 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: SCV004190055.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (1) PubMed: 15300854 Comment: This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an … (more) This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15300854]. (less)
Likely pathogenic (Jun 11, 2023)	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: SCV004265736.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 21056691‚ 16199547‚ 15713769‚ 24362816 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 21056691). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). (less)
Pathogenic (Apr 08, 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: SCV005134132.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: The c.1667+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 14 in the MLH1 gene. This nucleotide position … (more) The c.1667+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 14 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species, and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed in at least one individual with a personal and/or family history that is consistent with Lynch syndrome (Ambry internal data). Another alteration impacting the same donor site (c.1677+1G>A) has been detected in multiple individuals meeting Amsterdam criteria for Lynch syndrome (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less)

Comment:

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15300854].

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 21056691). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).

Comment:

The c.1667+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 14 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species, and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed in at least one individual with a personal and/or family history that is consistent with Lynch syndrome (Ambry internal data). Another alteration impacting the same donor site (c.1677+1G>A) has been detected in multiple individuals meeting Amsterdam criteria for Lynch syndrome (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, this variant 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

Title	Author	Journal	Year	Link
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.	Limburg PJ	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2011	PMID: 21056691
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.	Casey G	JAMA	2005	PMID: 15713769
RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1.	Sharp A	Human mutation	2004	PMID: 15300854

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.1667+2T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...