ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.884A>G (p.Lys295Arg)
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.
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(9); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.884A>G (p.Lys295Arg)
Variation ID: 89573 Accession: VCV000089573.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47798867 (GRCh38) [ NCBI UCSC ] 2: 48026006 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 17, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.884A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Lys295Arg missense NM_001281492.2:c.494A>G NP_001268421.1:p.Lys165Arg missense NM_001281493.2:c.-23A>G 5 prime UTR NM_001281494.2:c.-23A>G 5 prime UTR NC_000002.12:g.47798867A>G NC_000002.11:g.48026006A>G NG_007111.1:g.20721A>G LRG_219:g.20721A>G LRG_219t1:c.884A>G LRG_219p1:p.Lys295Arg P52701:p.Lys295Arg - Protein change
- K295R, K165R
- Other names
- p.K295R:AAA>AGA
- Canonical SPDI
- NC_000002.12:47798866:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00013
The Genome Aggregation Database (gnomAD) 0.00014
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 | ||
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HI score
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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. |
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MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9070 | 9377 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2015 | RCV000075042.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 7, 2021 | RCV000115445.16 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV000212636.23 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 29, 2023 | RCV000410872.11 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 28, 2022 | RCV000512927.29 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000524217.13 |
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. |
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Uncertain significance
(Nov 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: no, yes
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266213.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
colon cancer (present)
Age: 30-39 years
Observation 2:
Number of individuals with the variant: 1
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Likely benign
(Dec 09, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910671.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135797.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Mar 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149354.15
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
This variant is associated with the following publications: (PMID: 21437237, 18566915, 23621914, 16010685, 26333163, 26689913, 23047549, 26845104)
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Uncertain significance
(Oct 07, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536365.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.884A>G (p.K295R) variant has been reported in individuals with colorectal cancer, breast cancer, ovarian cancer, Lynch syndrome, or multiple colorectal adenomas (PMID: 26845104, … (more)
The MSH6 c.884A>G (p.K295R) variant has been reported in individuals with colorectal cancer, breast cancer, ovarian cancer, Lynch syndrome, or multiple colorectal adenomas (PMID: 26845104, 26689913, 30093976, 23047549, 18566915, 16010685, 28944238, 31391288). This variant has also been reported in 21/60466 breast cancer cases and 29/53461 healthy controls by a large case-control study (PMID: 33471991). A localization study demonstrated the normal function of the protein (PMID: 21437237). This variant was observed in 23/129030 chromosomes in the Non-Finnish European population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 89573). 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)
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Likely benign
(Aug 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695929.4
First in ClinVar: Oct 30, 2017 Last updated: Sep 17, 2022 |
Comment:
Variant summary: MSH6 c.884A>G (p.Lys295Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: MSH6 c.884A>G (p.Lys295Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 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 Non-Finnish European origin. c.884A>G has been reported in the literature associated with several types of cancer including but not limited to colorectal adenomas, Lynch syndrome, breast/ovarian cancer, colon cancer (Example: Lu_2015, Shirts_2015, Pal_2012, Nilbert_2009, Colley_2005, VanMarcke_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one ovarian cancer patient, a pathogenic BRCA2 variant was also found in the patient, providing supporting evidence for a benign role (Li_2019). One study reports that this variant did not affect MSH6 cellular localization but its proficiency in mismatch repair activity has not been addressed (Gassman_2011). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine submitters classified the variant as VUS while three classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Nov 18, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487810.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018953.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Jul 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601619.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00018 (23/129030 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.00018 (23/129030 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 16010685 (2005)), 18566915 (2009), and 26845104 (2016)) and ovarian cancer (PMID: 23047549 (2012)). The variant was also reported in a large breast cancer study in both cases and controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/MSH6/). This variant was reported to have no effect on MSH6 nuclear localization, however further studies are required to determine the global effect of this variant MSH6 protein function (PMID: 21437237 (2011)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or 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 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552286.6
First in ClinVar: Jul 27, 2022 Last updated: Feb 14, 2024 |
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Likely benign
(Jun 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000214730.8
First in ClinVar: Mar 24, 2015 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
(Mar 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539701.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 0.02% (12/66598) European chromosomes (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Aug 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001302619.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254335.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Uncertain significance
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608936.27
First in ClinVar: Oct 30, 2017 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552237.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Lys295Arg variant was identified in 4 of 8180 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colorectal cancer (Colley 2005, … (more)
The MSH6 p.Lys295Arg variant was identified in 4 of 8180 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colorectal cancer (Colley 2005, Nilbert 2009, Pal 2012, Shirts 2015). The variant was also identified in dbSNP (ID: rs267608051) as "With Uncertain significance allele ", ClinVar (classified as uncertain significance by InSight, GeneDx, Ambry Genetics, Invitae, Counsyl and five clinical laboratories), UMD-LSDB (2x as unclassified variant), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (2x) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or Zhejiang University, databases. The variant was identified in control databases in 26 of 276994 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 23 of 126552 chromosomes (freq: 0.0002), Finnish in 2 of 25790 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Lys295 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, in vitro study has shown that variant located in substantial amino-terminal region and does not disrupt MSH6 stability and localization signal. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer. | Kim SR | Cancer | 2020 | PMID: 32809219 |
Tumor sequencing is useful to refine the analysis of germline variants in unexplained high-risk breast cancer families. | Van Marcke C | Breast cancer research : BCR | 2020 | PMID: 32295625 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. | Li C | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 30584090 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
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 |
Cooperative nuclear localization sequences lend a novel role to the N-terminal region of MSH6. | Gassman NR | PloS one | 2011 | PMID: 21437237 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Rapid recognition of aberrant dHPLC elution profiles using the Transgenomic Navigator software. | Colley J | Human mutation | 2005 | PMID: 16010685 |
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Text-mined citations for rs267608051 ...
HelpRecord last updated Jun 17, 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.