VCV000925072.9 - ClinVar

NM_000249.4(MLH1):c.677+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.

(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.

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.677+2T>G

Variation ID: 925072 Accession: VCV000925072.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37012101 (GRCh38) [ NCBI UCSC ] 3: 37053592 (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	Jun 22, 2020	Feb 28, 2024	Apr 16, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.677+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001167617.3:c.383+2T>G		splice donor
NM_001167618.3:c.-47+2T>G		splice donor
NM_001167619.3:c.-47+2T>G		splice donor
NM_001258271.2:c.677+2T>G		splice donor
NM_001258273.2:c.-47+2T>G		splice donor
NM_001258274.3:c.-47+2T>G		splice donor
NM_001354615.2:c.-47+2T>G		splice donor
NM_001354616.2:c.-47+2T>G		splice donor
NM_001354617.2:c.-47+2T>G		splice donor
NM_001354618.2:c.-47+2T>G		splice donor
NM_001354619.2:c.-47+2T>G		splice donor
NM_001354620.2:c.383+2T>G		splice donor
NM_001354621.2:c.-140+2T>G		splice donor
NM_001354622.2:c.-253+2T>G		splice donor
NM_001354623.2:c.-253+2T>G		splice donor
NM_001354624.2:c.-150+2T>G		splice donor
NM_001354625.2:c.-150+2T>G		splice donor
NM_001354626.2:c.-150+2T>G		splice donor
NM_001354627.2:c.-150+2T>G		splice donor
NM_001354628.2:c.677+2T>G		splice donor
NM_001354629.2:c.578+2T>G		splice donor
NM_001354630.2:c.677+2T>G		splice donor
NC_000003.12:g.37012101T>G
NC_000003.11:g.37053592T>G
NG_007109.2:g.23752T>G
LRG_216:g.23752T>G
LRG_216t1:c.677+2T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:37012100: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

dbSNP: rs1553644277 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	5693	5754

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	Likely pathogenic (1)	criteria provided, single submitter	Jul 8, 2019	RCV001186811.3
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Apr 16, 2021	RCV001862943.6

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.
Likely pathogenic (Jul 08, 2019)	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: SCV001353391.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022	Comment: This variant causes a T>G nucleotide substitution at the +2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this … (more) This variant causes a T>G nucleotide substitution at the +2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Pathogenic (Apr 16, 2021)	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: SCV002195521.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 12624141‚ 15342696‚ 17312306‚ 27601186‚ 16199547‚ 15713769‚ 24362816 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 15342696, 17312306, 27601186, Invitae). ClinVar contains an entry for this variant (Variation ID: 925072). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 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)

Comment:

This variant causes a T>G nucleotide substitution at the +2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 15342696, 17312306, 27601186, Invitae). ClinVar contains an entry for this variant (Variation ID: 925072). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 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).

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
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.	Lagerstedt-Robinson K	Oncology reports	2016	PMID: 27601186
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
Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.	Lagerstedt Robinson K	Journal of the National Cancer Institute	2007	PMID: 17312306
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
BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.	Domingo E	Journal of medical genetics	2004	PMID: 15342696
Cancer risk in 348 French MSH2 or MLH1 gene carriers.	Parc Y	Journal of medical genetics	2003	PMID: 12624141

Text-mined citations for rs1553644277 ...

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.677+2T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1553644277 ...