ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.1754T>C (p.Leu585Pro)
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.1754T>C (p.Leu585Pro)
Variation ID: 89220 Accession: VCV000089220.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47799737 (GRCh38) [ NCBI UCSC ] 2: 48026876 (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 Oct 13, 2024 Oct 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.1754T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Leu585Pro missense NM_001281492.2:c.1364T>C NP_001268421.1:p.Leu455Pro missense NM_001281493.2:c.848T>C NP_001268422.1:p.Leu283Pro missense NM_001281494.2:c.848T>C NP_001268423.1:p.Leu283Pro missense NC_000002.12:g.47799737T>C NC_000002.11:g.48026876T>C NG_007111.1:g.21591T>C LRG_219:g.21591T>C LRG_219t1:c.1754T>C LRG_219p1:p.Leu585Pro P52701:p.Leu585Pro - Protein change
- L585P, L455P, L283P
- Other names
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- Canonical SPDI
- NC_000002.12:47799736:T:C
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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 |
9157 | 9471 |
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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Jun 24, 2024 | RCV000074683.14 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2024 | RCV000219463.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000491054.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000791380.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV001290557.9 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Dec 24, 2023 | RCV003128136.10 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003450930.2 | |
MSH6-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Nov 13, 2023 | RCV004537273.2 |
Submissions - Germline
Classification
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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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Likely 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: SCV004185555.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22581703]. This variant is expected to disrupt protein structure [Myriad … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22581703]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jan 16, 2023)
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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: SCV004221155.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The MSH6 c.1754T>C (p.Leu585Pro) variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in … (more)
The MSH6 c.1754T>C (p.Leu585Pro) variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 30877237 (2019), 22581703 (2012)) and ovarian/endometrial cancer (PMIDs: 30322717 (2018), 25617771 (2015)). It has also been described as a founder mutation associated with colorectal and endometrial cancer risk in Iceland (PMID: 28466842 (2017)). In addition, functional studies indicate this variant had deleterious effects on MSH6 protein stability and DNA mismatch repair activity (PMID: 22581703 (2012)). Based on the available information, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478629.2
First in ClinVar: Feb 12, 2021 Last updated: Mar 30, 2024 |
Comment:
Variant summary: MSH6 c.1754T>C (p.Leu585Pro) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of … (more)
Variant summary: MSH6 c.1754T>C (p.Leu585Pro) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250308 control chromosomes (gnomAD). c.1754T>C has been reported in the literature in individuals affected or suspected to be affected with Hereditary Nonpolyposis Colorectal Cancer (Lynch Sydrome; e.g., Kantelinin_2012, Cushman-Vokoun_2013, Haraldsdottir_2017, Pearlman_2019, Svensson_2022). However, no conclusive evidence for causality, such as cosegregation with disease in family studies, has been reported in these publications; therefore this evidence does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The variant has also been reported in an individual with endometrial cancer who had a family history of Lynch Syndrome-associated cancers and whose tumor tested MSH6-negative by IHC staining (e.g. Frolova_2015), a second individual with endometrial cancer (e.g., Kral_2023), and an individual with ovarian cancer (e.g. Carter_2018). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant impairs mismatch repair activity and results in unstable MSH6 protein when studied in vitro (e.g. Kantelinin_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30322717, 23773459, 25617771, 28466842, 22581703, 37153042, 30877237, 29887214, 35430768). ClinVar contains an entry for this variant (Variation ID: 89220). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 30, 2024)
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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: SCV000580096.7
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.L585P variant (also known as c.1754T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide … (more)
The p.L585P variant (also known as c.1754T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1754. The leucine at codon 585 is replaced by proline, an amino acid with similar properties. This alteration has been reported in conjunction with another MSH6 alteration (p.S677T) in an individual diagnosed with colon cancer at age 38 whose tumor showed high microsatellite instability and intact MLH1, MSH2, and PMS2 staining on immunohistochemistry (IHC), but inconclusive MSH6 staining. Furthermore, in vitro MMR assays showed that the p.L585P alteration displayed deficient MMR activity, while the second variant, p.S677T, displayed proficient MMR activity (Kantelinen J et al. Hum Mutat. 2012 Aug;33(8):1294-301). In addition, this alteration has been detected in several individuals diagnosed with colorectal and/or endometrial cancer whose tumor results revealed loss of MSH6 on IHC (Ambry internal data; Frolova AI et al. Gynecol. Oncol. 2015 Apr;137:7-13; Haraldsdottir S et al. Nat Commun. 2017 May;8:14755; Kral J et al. Oncol Lett, 2023 Jun;25:216). This alteration has also been identified in a cohort of 4,439 women with ovarian cancer (Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. In addition, based on internal structural analysis, p.L585P is predicted to strongly perturb the structure of the ATPase domain; however, the local sensitivity of the region has not been well characterized (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is likely to be pathogenic. (less)
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Likely pathogenic
(Dec 24, 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: SCV004198149.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 02, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551070.9
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 585 of the MSH6 protein (p.Leu585Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 585 of the MSH6 protein (p.Leu585Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 22581703, 23773459, 25617771, 30877237). ClinVar contains an entry for this variant (Variation ID: 89220). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 22581703). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 2024)
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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: SCV000279553.10
First in ClinVar: May 29, 2016 Last updated: Oct 13, 2024 |
Comment:
Observed in patients with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 22581703, 25617771, 28466842, 35430768, 30877237, 37153042); Common … (more)
Observed in patients with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 22581703, 25617771, 28466842, 35430768, 30877237, 37153042); Common founder variant in the Icelandic population (PMID: 28466842); Published functional studies demonstrate a damaging effect: deficient in mismatch repair activity and reduction of MSH6 protein (PMID: 22581703); Not observed at significant frequency in large population cohorts (gnomAD); 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: 22949387, 25617771, 29887214, 30322717, 29485237, 32719484, 17531815, 21120944, 34445333, 35430768, 37937776, 33471991, 23773459, 30877237, 28466842, 22581703, 37153042) (less)
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Likely pathogenic
(Feb 21, 2023)
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no assertion criteria provided
Method: clinical testing
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Endometrial carcinoma
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV003804331.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Number of individuals with the variant: 2
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Likely pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Lynch syndrome 5
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022208.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000179.3:c.1754T>C (chr2:47799737) in MSH6 was detected in 34 heterozygotes out of 58K WGS Icelanders (MAF= 0,029%). Following imputation in a set of 166K … (more)
The variant NM_000179.3:c.1754T>C (chr2:47799737) in MSH6 was detected in 34 heterozygotes out of 58K WGS Icelanders (MAF= 0,029%). Following imputation in a set of 166K Icelanders (102 imputed heterozygotes) we observed an association with colorectal cancer using 4991 cases and 314812 controls (OR= 9.62, P= 9.55e-12). This variant has been reported in ClinVar previously as pathogenic, likely pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PS4, PM2, PP3, PP5) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 102
Ethnicity/Population group: Icelandic
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Likely pathogenic
(Nov 13, 2023)
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no assertion criteria provided
Method: clinical testing
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MSH6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004715445.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The MSH6 c.1754T>C variant is predicted to result in the amino acid substitution p.Leu585Pro. This variant was reported in an individual with hereditary nonpolyposis colorectal … (more)
The MSH6 c.1754T>C variant is predicted to result in the amino acid substitution p.Leu585Pro. This variant was reported in an individual with hereditary nonpolyposis colorectal cancer (Kantelinen J et al 2012. PubMed ID: 22581703). In a large study from Iceland, the c.1754T>C variant was detected as a germline variant in 9 patients with mismatch repair deficiency colorectal cancer (Table 1 in Haraldsdottir et al 2017. PubMed ID: 28466842). This variant was also reported in an individual with ovarian cancer (Carter NJ et al 2018. PubMed ID: 30322717) and a patient with endometrial cancer with a family history of Lynch Syndrome-associated cancers (Frolova AI et al 2015. PubMed ID: 25617771). In vitro mismatch repair assays indicate this variant impacts protein function (Kantelinen J et al 2012. PubMed ID: 22581703). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is reported by most labs in ClinVar as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/89220/). This variant is interpreted as likely pathogenic. (less)
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Uncertain significance
(May 01, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887368.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment:
MSH6 NM_000179.2:c.1754T>C has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated … (more)
MSH6 NM_000179.2:c.1754T>C has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Germline multigene panel testing of patients with endometrial cancer. | Kral J | Oncology letters | 2023 | PMID: 37153042 |
Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort. | Svensson S | Genes, chromosomes & cancer | 2022 | PMID: 35430768 |
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 |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome. | Pearlman R | Journal of medical genetics | 2019 | PMID: 30877237 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. | Shirts BH | American journal of human genetics | 2018 | PMID: 29887214 |
Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. | Boland PM | CA: a cancer journal for clinicians | 2018 | PMID: 29485237 |
Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. | Haraldsdottir S | Nature communications | 2017 | PMID: 28466842 |
Impact of an immunohistochemistry-based universal screening protocol for Lynch syndrome in endometrial cancer on genetic counseling and testing. | Frolova AI | Gynecologic oncology | 2015 | PMID: 25617771 |
Clinical utility of KRAS and BRAF mutations in a cohort of patients with colorectal neoplasms submitted for microsatellite instability testing. | Cushman-Vokoun AM | Clinical colorectal cancer | 2013 | PMID: 23773459 |
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 |
Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients. | Kantelinen J | Human mutation | 2012 | PMID: 22581703 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
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Text-mined citations for rs587779220 ...
HelpRecord last updated Oct 13, 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.