VCV000184803.40 - ClinVar

NM_000179.3(MSH6):c.980C>G (p.Thr327Ser)

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.

(10)

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(7); Likely benign(3)

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.980C>G (p.Thr327Ser)

Variation ID: 184803 Accession: VCV000184803.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47798963 (GRCh38) [ NCBI UCSC ] 2: 48026102 (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 19, 2017	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.980C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Thr327Ser	missense
NM_001281492.2:c.590C>G	NP_001268421.1:p.Thr197Ser	missense
NM_001281493.2:c.74C>G	NP_001268422.1:p.Thr25Ser	missense
NM_001281494.2:c.74C>G	NP_001268423.1:p.Thr25Ser	missense
NC_000002.12:g.47798963C>G
NC_000002.11:g.48026102C>G
NG_007111.1:g.20817C>G
LRG_219:g.20817C>G
LRG_219t1:c.980C>G	LRG_219p1:p.Thr327Ser

... more HGVS ... less HGVS

Protein change

T327S, T25S, T197S

Other names

Canonical SPDI

NC_000002.12:47798962:C: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA016745 dbSNP: rs369568820 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 cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 12, 2024	RCV000164123.10
Hereditary nonpolyposis colorectal neoplasms	Likely benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000204780.14
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 1, 2024	RCV000479969.21
Lynch syndrome 5	Uncertain significance (1)	criteria provided, single submitter	Jun 1, 2022	RCV003137692.1
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	Oct 12, 2021	RCV003150013.2
MSH6-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 2, 2023	RCV004528909.1
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 27, 2023	RCV003995316.2

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 (Oct 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003837640.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Aug 22, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889512.4 First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 33471991‚ 31391288‚ 23621914‚ 23047549 Comment: In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), a Lynch syndrome-associated cancer (PMID: 31391288 (2020)), and … (more) In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), a Lynch syndrome-associated cancer (PMID: 31391288 (2020)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6)). The frequency of this variant in the general population, 0.000039 (5/129124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Likely benign (Feb 12, 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: SCV000214738.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 23047549‚ 23621914 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 (Jun 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807734.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS4 supporting, PM2 moderated, BP4 supporting Number of individuals with the variant: 1 Clinical Features: Colon cancer (present) , Hepatic steatosis (present) , Renal cyst (present) , Colon adenocarcinoma (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Uncertain significance (Jul 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MSH6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004108498.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MSH6 c.980C>G variant is predicted to result in the amino acid substitution p.Thr327Ser. This variant has been reported in individuals with ovarian or pancreatic … (more) The MSH6 c.980C>G variant is predicted to result in the amino acid substitution p.Thr327Ser. This variant has been reported in individuals with ovarian or pancreatic cancer (Table S1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Grant et al. 2015. PubMed ID: 25479140). An MSH6-specific in silico tool predicts that this variant does not impact protein function (Table 8, Terui et al. 2013. PubMed: 23621914). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026102-C-G) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184803/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Jan 26, 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: SCV000911932.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 23047549‚ 25479140 Comment: This missense variant replaces threonine with serine at codon 327 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces threonine with serine at codon 327 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 25479140) in the literature. This variant has also been identified in 6/282796 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)
Likely benign (Feb 01, 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: SCV000260205.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain Significance (Oct 27, 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: SCV004837525.1 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 (4) PubMed: 23047549‚ 25479140‚ 31391288‚ 33471991 Comment: This missense variant replaces threonine with serine at codon 327 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces threonine with serine at codon 327 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140), and unspecified cancer (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/282796 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: 5
Likely benign (Mar 01, 2024)	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: SCV004146077.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: MSH6: PM2:Supporting, BP1, BP4 Number of individuals with the variant: 2
Uncertain significance (Dec 06, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568902.10 First in ClinVar: Apr 29, 2017 Last updated: Sep 29, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian, pancreatic, or prostate cancer (PMID: 23047549, 25479140, 26689913); This variant is associated with the following publications: (PMID: 23621914, 25479140, 23047549, 21437237, 26689913) (less)

Comment:

In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), a Lynch syndrome-associated cancer (PMID: 31391288 (2020)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6)). The frequency of this variant in the general population, 0.000039 (5/129124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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:

The MSH6 c.980C>G variant is predicted to result in the amino acid substitution p.Thr327Ser. This variant has been reported in individuals with ovarian or pancreatic cancer (Table S1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Grant et al. 2015. PubMed ID: 25479140). An MSH6-specific in silico tool predicts that this variant does not impact protein function (Table 8, Terui et al. 2013. PubMed: 23621914). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026102-C-G) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184803/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This missense variant replaces threonine with serine at codon 327 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 25479140) in the literature. This variant has also been identified in 6/282796 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 missense variant replaces threonine with serine at codon 327 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140), and unspecified cancer (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/282796 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:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian, pancreatic, or prostate cancer (PMID: 23047549, 25479140, 26689913); This variant is associated with the following publications: (PMID: 23621914, 25479140, 23047549, 21437237, 26689913)

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 threonine with serine at codon 327 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140), and unspecified cancer (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/282796 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
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
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.	Li S	Journal of medical genetics	2020	PMID: 31391288
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.	Grant RC	Gastroenterology	2015	PMID: 25479140
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
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.	Pal T	British journal of cancer	2012	PMID: 23047549

Text-mined citations for rs369568820 ...

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.980C>G (p.Thr327Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369568820 ...