ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.1705_1706del (p.Phe569fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.1705_1706del (p.Phe569fs)
Variation ID: 156507 Accession: VCV000156507.22
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 2p16.3 2: 47799685-47799686 (GRCh38) [ NCBI UCSC ] 2: 48026824-48026825 (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 Oct 20, 2014 May 1, 2024 Dec 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.1705_1706del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Phe569fs frameshift NM_000179.2:c.1705_1706delTT NM_001281492.2:c.1315_1316del NP_001268421.1:p.Phe439fs frameshift NM_001281493.2:c.799_800del NP_001268422.1:p.Phe267fs frameshift NM_001281494.2:c.799_800del NP_001268423.1:p.Phe267fs frameshift NC_000002.12:g.47799688_47799689del NC_000002.11:g.48026827_48026828del NG_007111.1:g.21542_21543del LRG_219:g.21542_21543del - Protein change
- F267fs, F439fs
- Other names
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- Canonical SPDI
- NC_000002.12:47799684:TTTTT:TTT
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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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
9037 | 9343 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (1) |
no assertion criteria provided
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Jul 24, 2014 | RCV000144627.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2022 | RCV000216742.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2023 | RCV000542464.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000780461.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV001258039.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2023 | RCV003462054.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 12, 2023 | RCV003137645.4 |
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
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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
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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
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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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Pathogenic
(Dec 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917728.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The variant, MSH6 c.1705_1706delTT (p.Phe569HisfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of … (more)
Variant summary: The variant, MSH6 c.1705_1706delTT (p.Phe569HisfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1784delT (p.Leu595fsX15), c.2150_2153delTCAG (p.Val717fsX18)). The variant allele was found at a frequency of 3.2e-05 in 30970 control chromosomes. c.1705_1706delTT has been reported in the literature in an individual affected with colon cancer (Foley_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary non-polyposis colorectal cancer, type 5
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434867.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is predicted to introduce a premature translation termination codon and is extremely rare in general population. Therefore, … (more)
The c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is predicted to introduce a premature translation termination codon and is extremely rare in general population. Therefore, the c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is classified as pathogenic. (less)
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Pathogenic
(May 12, 2023)
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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: SCV003926442.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individual(s) with a personal or family history consistent with pathogenic variants in this gene (Foley et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24362816, 31447099, 18269114, 34594420, 32686686, 32832836, 26023681) (less)
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Pathogenic
(Aug 15, 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: SCV004187407.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Mar 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195825.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003822227.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 13, 2021)
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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: SCV000905451.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual referred for hereditary colorectal cancer screening (PMID: 28502729) and in an individual affected with colorectal cancer (PMID: 26023681). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 08, 2023)
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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: SCV000624682.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe569Hisfs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Phe569Hisfs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs587783056, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 156507). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004837740.1
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)
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Comment:
The c.1705_1706del (p.Phe569Hisfs*7) variant in the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a … (more)
The c.1705_1706del (p.Phe569Hisfs*7) variant in the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Phe569Hisfs*7), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 28514183, 23598716, 26023681, 31447099, 25479140, 30917047). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 156507). The variant is rare in the general population according to gnomAD (1/31404). Therefore, the c.1705_1706del (p.Phe569Hisfs*7) variant of MSH6 has been classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 24, 2022)
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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: SCV000274941.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.1705_1706delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides between positions 1705 and 1706, … (more)
The c.1705_1706delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides between positions 1705 and 1706, causing a translational frameshift with a predicted alternate stop codon (p.F569Hfs*7). This pathogenic mutation has been detected in an individual with colon cancer diagnosed at age 52 and a family history of endometrial cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189954.1
First in ClinVar: Oct 20, 2014 Last updated: Oct 20, 2014 |
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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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Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies. | Sarode VR | Archives of pathology & laboratory medicine | 2019 | PMID: 30917047 |
Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. | Latham A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30376427 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing. | Rey JM | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28502729 |
Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. | Foley SB | EBioMedicine | 2015 | PMID: 26023681 |
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges. | Marquez E | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23598716 |
Risks of Lynch syndrome cancers for MSH6 mutation carriers. | Baglietto L | Journal of the National Cancer Institute | 2010 | PMID: 20028993 |
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts. | Devlin LA | The Ulster medical journal | 2008 | PMID: 18269114 |
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Text-mined citations for rs587783056 ...
HelpRecord last updated May 08, 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.