VCV000428433.28 - ClinVar

NM_000179.3(MSH6):c.2759del (p.Lys920fs)

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.

(6)

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_000179.3(MSH6):c.2759del (p.Lys920fs)

Variation ID: 428433 Accession: VCV000428433.28

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2p16.3 2: 47800739 (GRCh38) [ NCBI UCSC ] 2: 48027878 (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 25, 2017	May 1, 2024	Jul 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.2759del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Lys920fs	frameshift
NM_000179.2:c.2759delA
NM_001281492.2:c.2369del	NP_001268421.1:p.Lys790fs	frameshift
NM_001281493.2:c.1853del	NP_001268422.1:p.Lys618fs	frameshift
NM_001281494.2:c.1853del	NP_001268423.1:p.Lys618fs	frameshift
NC_000002.12:g.47800742del
NC_000002.11:g.48027881del
NG_007111.1:g.22596del
LRG_219:g.22596del

... more HGVS ... less HGVS

Protein change

K790fs, K920fs, K618fs

Other names

Canonical SPDI

NC_000002.12:47800738:AAAA:AAA

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

ClinGen: CA645369255 dbSNP: rs1114167794 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 cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2022	RCV000491468.3
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2022	RCV001385943.5
Lynch syndrome 5	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 25, 2023	RCV002466258.2
Uterine corpus cancer	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128158.1
Lynch syndrome	Likely pathogenic (1)	criteria provided, single submitter	May 8, 2019	RCV004017645.2

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.
Likely pathogenic (Feb 01, 2013)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	Arcensus Accession: SCV002564552.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Jul 25, 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: SCV004187258.1 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.
Pathogenic (Jun 20, 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: SCV000580366.6 First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024	Comment: The c.2759delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 2759, causing … (more) The c.2759delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 2759, causing a translational frameshift with a predicted alternate stop codon (p.K920Rfs*25).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
Likely Pathogenic (May 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847759.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Lys920ArgfsX25 variant in MSH6 has not been previously reported in individuals with Lynch Syndrome and was absent from large population studies. This variant has … (more) The p.Lys920ArgfsX25 variant in MSH6 has not been previously reported in individuals with Lynch Syndrome and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 428433). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 920 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2. (less)
Pathogenic (Feb 23, 2022)	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: SCV001585963.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 18269114‚ 24362816 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428433). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428433). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys920Argfs*25) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). (less)
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Uterine corpus cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804333.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic

Comment:

The c.2759delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 2759, causing a translational frameshift with a predicted alternate stop codon (p.K920Rfs*25).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Comment:

The p.Lys920ArgfsX25 variant in MSH6 has not been previously reported in individuals with Lynch Syndrome and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 428433). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 920 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428433). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys920Argfs*25) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 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
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

Text-mined citations for rs1114167794 ...

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.2759del (p.Lys920fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1114167794 ...