VCV000089168.41 - ClinVar

NM_000179.3(MSH6):c.1082G>A (p.Arg361His)

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.

(11)

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.

Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000179.3(MSH6):c.1082G>A (p.Arg361His)

Variation ID: 89168 Accession: VCV000089168.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47799065 (GRCh38) [ NCBI UCSC ] 2: 48026204 (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	Mar 24, 2015	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.1082G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Arg361His	missense
NM_001281492.2:c.692G>A	NP_001268421.1:p.Arg231His	missense
NM_001281493.2:c.176G>A	NP_001268422.1:p.Arg59His	missense
NM_001281494.2:c.176G>A	NP_001268423.1:p.Arg59His	missense
NC_000002.12:g.47799065G>A
NC_000002.11:g.48026204G>A
NG_007111.1:g.20919G>A
LRG_219:g.20919G>A
LRG_219t1:c.1082G>A	LRG_219p1:p.Arg361His

... more HGVS ... less HGVS

Protein change

R361H, R231H, R59H

Other names

Canonical SPDI

NC_000002.12:47799064:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA007978 dbSNP: rs63750440 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.
Lynch syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000074629.8
Lynch syndrome 5	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 30, 2023	RCV000409637.4
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000487116.16
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000567227.12
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Jan 18, 2024	RCV000701439.9
Endometrial carcinoma	Uncertain significance (1)	criteria provided, single submitter	Sep 5, 2023	RCV003466931.1
MSH6-related disorder	Uncertain significance (1)	no assertion criteria provided	Apr 19, 2024	RCV004739330.1

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.
Uncertain significance (May 01, 2018)	criteria provided, single submitter (Shirts BH et al. (Am J Hum Genet 2018)) Method: clinical testing	Lynch syndrome Affected status: yes Allele origin: somatic	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000887361.1 First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015	Publications: PubMed (1) PubMed: 29887214 Comment: MSH6 NM_000179.2:c.1082G>A has a 48.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, and 0.16 to … (more) MSH6 NM_000179.2:c.1082G>A has a 48.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, and 0.16 to 1, generated from evidence of seeing this as a somatic mutation in three independent tumors two without loss of heterozygosity and one with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. (less)
Uncertain significance (Mar 30, 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: SCV004019092.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Sep 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195529.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Benign (Jan 18, 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: SCV000830240.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain Significance (Dec 01, 2023)	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: SCV004842902.1 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 (1) PubMed: 17498565 Comment: This missense variant replaces arginine with histidine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with histidine at codon 361 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 hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has also been identified in 4/251054 chromosomes 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: 6
Likely benign (Feb 01, 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: SCV000670019.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 17498565 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002585789.15 First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024	Comment: MSH6: PM2, BP4 Number of individuals with the variant: 1
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000571658.5 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: This variant is denoted MSH6 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to … (more) This variant is denoted MSH6 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in an individual with a personal history of hepatic and gastric cancer (Koehler 2007). MSH6 Arg361His was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Arg361His is located in the nuclear localization signals region (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg361His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
Uncertain significance (Aug 05, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489034.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 26333163‚ 17498565‚ 23621914‚ 22290698
Uncertain significance (Mar 23, 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: SCV000690172.6 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 17498565 Comment: This missense variant replaces arginine with histidine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with histidine at codon 361 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 hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has been identified in 4/251054 chromosomes 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 (Apr 19, 2024)	no assertion criteria provided Method: clinical testing	MSH6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005359327.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MSH6 c.1082G>A variant is predicted to result in the amino acid substitution p.Arg361His. This variant was reported in a study of hereditary cancer variants … (more) The MSH6 c.1082G>A variant is predicted to result in the amino acid substitution p.Arg361His. This variant was reported in a study of hereditary cancer variants in biliary tract cancer and was classified as a variant of uncertain significance (VUS) (Okawa et al. 2023. PubMed ID: 36243179, Supplementary Table 2). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant was classified as VUS by the vast majority of the laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/89168/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

MSH6 NM_000179.2:c.1082G>A has a 48.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, and 0.16 to 1, generated from evidence of seeing this as a somatic mutation in three independent tumors two without loss of heterozygosity and one with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

Comment:

This missense variant replaces arginine with histidine at codon 361 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 hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has also been identified in 4/251054 chromosomes 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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is denoted MSH6 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in an individual with a personal history of hepatic and gastric cancer (Koehler 2007). MSH6 Arg361His was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Arg361His is located in the nuclear localization signals region (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg361His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Comment:

This missense variant replaces arginine with histidine at codon 361 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 hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has been identified in 4/251054 chromosomes 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:

The MSH6 c.1082G>A variant is predicted to result in the amino acid substitution p.Arg361His. This variant was reported in a study of hereditary cancer variants in biliary tract cancer and was classified as a variant of uncertain significance (VUS) (Okawa et al. 2023. PubMed ID: 36243179, Supplementary Table 2). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant was classified as VUS by the vast majority of the laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/89168/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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:

This missense variant replaces arginine with histidine at codon 361 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 hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has been identified in 4/251054 chromosomes 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.	Niroula A	Human mutation	2015	PMID: 26333163
CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.	Terui H	Journal of biomedical science	2013	PMID: 23621914
Classification of mismatch repair gene missense variants with PON-MMR.	Ali H	Human mutation	2012	PMID: 22290698
A new interphase fluorescence in situ hybridization approach for genomic rearrangements involving MLH1 and MSH6 in hereditary nonpolyposis colorectal cancer-suspected mutation-negative patients.	Koehler U	Cancer genetics and cytogenetics	2007	PMID: 17498565

Text-mined citations for rs63750440 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.1082G>A (p.Arg361His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750440 ...