This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3260C>A (p.Pro1087His)
Germline
Classification
Help
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.
(15)
Help
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); Likely benign(4)
Uncertain significance(8); Likely benign(4)
15
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.3260C>A (p.Pro1087His)
Variation ID: 127584 Accession: VCV000127584.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p16.3 2: 47803507 (GRCh38) [ NCBI UCSC ] 2: 48030646 (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 9, 2014 Oct 8, 2024 May 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3260C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Pro1087His missense NM_001281492.2:c.2870C>A NP_001268421.1:p.Pro957His missense NM_001281493.2:c.2354C>A NP_001268422.1:p.Pro785His missense NM_001281494.2:c.2354C>A NP_001268423.1:p.Pro785His missense NC_000002.12:g.47803507C>A NC_000002.11:g.48030646C>A NG_007111.1:g.25361C>A LRG_219:g.25361C>A LRG_219t1:c.3260C>A LRG_219p1:p.Pro1087His - Protein change
- P1087H, P785H, P957H
- Other names
-
p.P1087H:CCC>CAC
- Canonical SPDI
- NC_000002.12:47803506:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 2, 2023 | RCV000115410.29 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
May 10, 2024 | RCV000121584.29 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 27, 2024 | RCV000168382.21 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 14, 2023 | RCV000589544.22 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 5, 2024 | RCV003997248.2 | |
|
MSH6-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Jun 3, 2024 | RCV004528800.2 |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 17, 2020 | RCV001808341.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 9, 2021 | RCV001787917.8 |
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
(Feb 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mismatch repair cancer syndrome 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030249.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010095.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Likely benign
(May 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695851.7
First in ClinVar: Mar 17, 2018 Last updated: Aug 11, 2024 |
Comment:
Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the … (more)
Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 327960 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3260C>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer, biliary tract cancer, and colorectal cancer (example, Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018, Kwong_2020, Ackay_2021, Djursby_2022, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 35904628, 24448499, 32068069, 26689913, 36243179, 30072391, 27398995, 23621914). ClinVar contains an entry for this variant (Variation ID: 127584). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
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Uncertain significance
(Mar 12, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002527997.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.3260C>A (p.P1087H) variant has been reported in individuals with breast cancer, stomach adenocarcinoma, acute myeloid leukemia, endometrial cancer, colorectal cancer, extrahepatic bile duct … (more)
The MSH6 c.3260C>A (p.P1087H) variant has been reported in individuals with breast cancer, stomach adenocarcinoma, acute myeloid leukemia, endometrial cancer, colorectal cancer, extrahepatic bile duct cancer, and pancreatic cancer (PMID: 26689913, 27398995, 30072391, 32658311, 32068069, 31666926, 29684080). However, the variant was also reported in healthy controls (PMID: 32980694, 24728327). It was observed in 35/282836 across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 127584). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Likely benign
(Apr 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149319.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, 24728327, 23621914, 27398995, 26689913, 17594722, 10508506, 17531815, 22851212, 12019211, 21120944, 22102614, 29596542, 30072391) (less)
|
|
|
Uncertain significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552335.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
|
|
|
Uncertain significance
(May 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537572.7
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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)
|
|
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Likely benign
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219073.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
|
|
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Uncertain significance
(Jan 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059505.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
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Uncertain significance
(Aug 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601568.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial … (more)
In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial cancer (PMID: 27398995 (2016)), and breast cancer (PMIDs: 26689913 (2015), 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00051 (18/35424 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
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Uncertain Significance
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004835030.1
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)
|
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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: 32
|
|
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Likely benign
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184771.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
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)
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691937.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Uncertain significance
(Jun 03, 2024)
|
no assertion criteria provided
Method: clinical testing
|
MSH6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805886.3
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio … (more)
The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio et al. 2016. PubMed ID: 27398995), breast cancer (Kwong et al. 2020. PubMed ID: 32068069), colon cancer (Patel et al. 2018. PubMed ID: 30072391) and various other cancer types (Lu et al. 2015. PubMed ID: 26689913). However, this variant was also reported in individuals from a healthy control cohort (Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity, from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127584/). 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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not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085780.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Comment:
Comment:
Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 327960 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3260C>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer, biliary tract cancer, and colorectal cancer (example, Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018, Kwong_2020, Ackay_2021, Djursby_2022, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 35904628, 24448499, 32068069, 26689913, 36243179, 30072391, 27398995, 23621914). ClinVar contains an entry for this variant (Variation ID: 127584). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, 24728327, 23621914, 27398995, 26689913, 17594722, 10508506, 17531815, 22851212, 12019211, 21120944, 22102614, 29596542, 30072391)
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial cancer (PMID: 27398995 (2016)), and breast cancer (PMIDs: 26689913 (2015), 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00051 (18/35424 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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:
The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio et al. 2016. PubMed ID: 27398995), breast cancer (Kwong et al. 2020. PubMed ID: 32068069), colon cancer (Patel et al. 2018. PubMed ID: 30072391) and various other cancer types (Lu et al. 2015. PubMed ID: 26689913). However, this variant was also reported in individuals from a healthy control cohort (Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity, from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127584/). 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 variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Variant summary: MSH6 c.3260C>A (p.Pro1087His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 327960 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3260C>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, endometrial cancer, biliary tract cancer, and colorectal cancer (example, Lu_2015, Kanchi_2014, Rubio_2016, Patel_2018, Kwong_2020, Ackay_2021, Djursby_2022, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 35904628, 24448499, 32068069, 26689913, 36243179, 30072391, 27398995, 23621914). ClinVar contains an entry for this variant (Variation ID: 127584). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10537275, 24728327, 23621914, 27398995, 26689913, 17594722, 10508506, 17531815, 22851212, 12019211, 21120944, 22102614, 29596542, 30072391)
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 30072391 (2018), 35904628 (2022)), gastric cancer (PMID: 26689913 (2015)), endometrial cancer (PMID: 27398995 (2016)), and breast cancer (PMIDs: 26689913 (2015), 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00051 (18/35424 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces proline with histidine at codon 1087 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995), breast cancer (PMID: 26689913, 32068069, 32658311), gastric cancer (PMID: 26689913), acute myeloid leukemia (PMID: 26689913), or colorectal cancer (PMID: 30072391), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 35/282836 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:
The MSH6 c.3260C>A variant is predicted to result in the amino acid substitution p.Pro1087His. This variant has been reported in individuals with endometrial cancer (Rubio et al. 2016. PubMed ID: 27398995), breast cancer (Kwong et al. 2020. PubMed ID: 32068069), colon cancer (Patel et al. 2018. PubMed ID: 30072391) and various other cancer types (Lu et al. 2015. PubMed ID: 26689913). However, this variant was also reported in individuals from a healthy control cohort (Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity, from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127584/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
| Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer. | Djursby M | Human genetics | 2022 | PMID: 35904628 |
| 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 |
| Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
| Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
| Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel. | Kwong A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32068069 |
| Germline mutations in cancer-predisposition genes in patients with biliary tract cancer. | Terashima T | Oncotarget | 2019 | PMID: 31666926 |
| Tumor Molecular Testing Guides Anti-PD-1 Therapy and Provides Evidence for Pathogenicity of Mismatch Repair Variants. | Patel SA | The oncologist | 2018 | PMID: 30072391 |
| Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
| Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer. | Rubio I | Oncology | 2016 | PMID: 27398995 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| Integrated analysis of germline and somatic variants in ovarian cancer. | Kanchi KL | Nature communications | 2014 | PMID: 24448499 |
| Functional analysis in mouse embryonic stem cells reveals wild-type activity for three MSH6 variants found in suspected Lynch syndrome patients. | Wielders EA | PloS one | 2013 | PMID: 24040339 |
| 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 |
| Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment. | Belvederesi L | Familial cancer | 2012 | PMID: 22851212 |
| A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
| Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. | Kansikas M | Human mutation | 2011 | PMID: 21120944 |
| Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
| Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
| Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome. | Kariola R | Human molecular genetics | 2002 | PMID: 12019211 |
| Germ-line msh6 mutations in colorectal cancer families. | Kolodner RD | Cancer research | 1999 | PMID: 10537275 |
| Familial endometrial cancer in female carriers of MSH6 germline mutations. | Wijnen J | Nature genetics | 1999 | PMID: 10508506 |
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Text-mined citations for rs63750753 ...
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Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.