VCV000648638.6 - ClinVar

NM_000179.3(MSH6):c.458-1G>T

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.

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_000179.3(MSH6):c.458-1G>T

Variation ID: 648638 Accession: VCV000648638.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47795893 (GRCh38) [ NCBI UCSC ] 2: 48023032 (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	Aug 14, 2019	Feb 20, 2024	Aug 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.458-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001281492.2:c.238-2718G>T		intron variant
NM_001281493.2:c.-279-2718G>T		intron variant
NM_001281494.2:c.-445-1G>T		splice acceptor
NM_001406795.1:c.554-1G>T		splice acceptor
NM_001406796.1:c.458-1G>T		splice acceptor
NM_001406797.1:c.161-1G>T		splice acceptor
NM_001406798.1:c.458-1G>T		splice acceptor
NM_001406799.1:c.-68-1G>T		splice acceptor
NM_001406800.1:c.458-1G>T		splice acceptor
NM_001406801.1:c.161-1G>T		splice acceptor
NM_001406802.1:c.554-1G>T		splice acceptor
NM_001406803.1:c.458-1G>T		splice acceptor
NM_001406804.1:c.380-1G>T		splice acceptor
NM_001406805.1:c.161-1G>T		splice acceptor
NM_001406806.1:c.-68-1G>T		splice acceptor
NM_001406807.1:c.-69G>T		5 prime UTR
NM_001406808.1:c.458-1G>T		splice acceptor
NM_001406809.1:c.458-1G>T		splice acceptor
NM_001406811.1:c.-279-2718G>T		intron variant
NM_001406812.1:c.-279-2718G>T		intron variant
NM_001406813.1:c.464-1G>T		splice acceptor
NM_001406814.1:c.-537-1G>T		splice acceptor
NM_001406815.1:c.-279-2718G>T		intron variant
NM_001406816.1:c.-279-2718G>T		intron variant
NM_001406817.1:c.458-1G>T		splice acceptor
NM_001406818.1:c.161-1G>T		splice acceptor
NM_001406819.1:c.161-1G>T		splice acceptor
NM_001406820.1:c.161-1G>T		splice acceptor
NM_001406821.1:c.161-1G>T		splice acceptor
NM_001406822.1:c.161-1G>T		splice acceptor
NM_001406823.1:c.-279-2718G>T		intron variant
NM_001406824.1:c.161-1G>T		splice acceptor
NM_001406825.1:c.161-1G>T		splice acceptor
NM_001406826.1:c.290-1G>T		splice acceptor
NM_001406827.1:c.161-1G>T		splice acceptor
NM_001406828.1:c.161-1G>T		splice acceptor
NM_001406829.1:c.-279-2718G>T		intron variant
NM_001406830.1:c.161-1G>T		splice acceptor
NM_001407362.1:c.458-1G>T		splice acceptor
NC_000002.12:g.47795893G>T
NC_000002.11:g.48023032G>T
NG_007111.1:g.17747G>T
LRG_219:g.17747G>T
LRG_219t1:c.458-1G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:47795892: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

dbSNP: rs267608035 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.
MSH6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9161	9479

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 nonpolyposis colorectal neoplasms	Likely pathogenic (1)	criteria provided, single submitter	Dec 8, 2018	RCV000803405.7
Lynch syndrome 5	Likely pathogenic (1)	criteria provided, single submitter	Aug 10, 2023	RCV003453672.1

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.
Likely pathogenic (Aug 10, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004185570.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more) This variant is considered likely 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. (less)
Likely pathogenic (Dec 08, 2018)	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: SCV000943274.3 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 16199547‚ 18269114‚ 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). Disruption of this splice site has been observed in combination with another MSH6 variant in an individual affected with¬†constitutional mismatch repair deficiency syndrome¬†(PMID:¬†17259933). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)

Comment:

This variant is considered likely 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.

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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). Disruption of this splice site has been observed in combination with another MSH6 variant in an individual affected with¬†constitutional mismatch repair deficiency syndrome¬†(PMID:¬†17259933). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

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
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.	Devlin LA	The Ulster medical journal	2008	PMID: 18269114
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs267608035 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.458-1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608035 ...