VCV000455195.23 - ClinVar

NM_000179.3(MSH6):c.2383A>G (p.Ile795Val)

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.

(5)

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.

Uncertain significance

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.2383A>G (p.Ile795Val)

Variation ID: 455195 Accession: VCV000455195.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47800366 (GRCh38) [ NCBI UCSC ] 2: 48027505 (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 26, 2017	May 1, 2024	Jan 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.2383A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Ile795Val	missense
NM_001281492.2:c.1993A>G	NP_001268421.1:p.Ile665Val	missense
NM_001281493.2:c.1477A>G	NP_001268422.1:p.Ile493Val	missense
NM_001281494.2:c.1477A>G	NP_001268423.1:p.Ile493Val	missense
NC_000002.12:g.47800366A>G
NC_000002.11:g.48027505A>G
NG_007111.1:g.22220A>G
LRG_219:g.22220A>G
LRG_219t1:c.2383A>G	LRG_219p1:p.Ile795Val

... more HGVS ... less HGVS

Protein change

I795V, I493V, I665V

Other names

Canonical SPDI

NC_000002.12:47800365:A: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA46711010 dbSNP: rs865931684 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	9159	9475

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	Uncertain significance (1)	criteria provided, single submitter	Jan 7, 2024	RCV000558096.16
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV001015335.16
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 13, 2021	RCV001811026.13
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 3, 2024	RCV004003678.2

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.
Uncertain significance (Sep 13, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002048060.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The MSH6 c.2383A>G; p.Ile795Val variant (rs865931684), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 455195). This … (more) The MSH6 c.2383A>G; p.Ile795Val variant (rs865931684), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 455195). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 795 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). Another amino acid substitutions at this codon (p.Ile795Thr) has been reported in an individual affected with pancreatic cancer, although its clinical significance was considered uncertain (Shindo 2017). Due to limited information, the clinical significance of the p.Ile795Val variant is uncertain at this time. References: Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289. (less)
Uncertain significance (Dec 13, 2023)	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: SCV001342493.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 26898890‚ 33471991 Comment: This missense variant replaces isoleucine with valine at codon 795 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces isoleucine with valine at codon 795 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 07, 2024)	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: SCV000624755.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 795 of the MSH6 protein (p.Ile795Val). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 795 of the MSH6 protein (p.Ile795Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 455195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Jan 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004834287.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 26898890‚ 33471991 Comment: This missense variant replaces isoleucine with valine at codon 795 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces isoleucine with valine at codon 795 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1
Uncertain significance (Jul 26, 2023)	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: SCV001176157.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 26898890‚ 33471991 Comment: The p.I795V variant (also known as c.2383A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide … (more) The p.I795V variant (also known as c.2383A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2383. The isoleucine at codon 795 is replaced by valine, an amino acid with highly similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 40 and had a family history of breast cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). In another study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The MSH6 c.2383A>G; p.Ile795Val variant (rs865931684), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 455195). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 795 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). Another amino acid substitutions at this codon (p.Ile795Thr) has been reported in an individual affected with pancreatic cancer, although its clinical significance was considered uncertain (Shindo 2017). Due to limited information, the clinical significance of the p.Ile795Val variant is uncertain at this time. References: Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289.

Comment:

This missense variant replaces isoleucine with valine at codon 795 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 795 of the MSH6 protein (p.Ile795Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 455195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.I795V variant (also known as c.2383A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2383. The isoleucine at codon 795 is replaced by valine, an amino acid with highly similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 40 and had a family history of breast cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). In another study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.	Caminsky NG	Human mutation	2016	PMID: 26898890

Text-mined citations for rs865931684 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.2383A>G (p.Ile795Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs865931684 ...