Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2013 by
International …
for
Lynch Syndrome
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)
Variation ID: 29654 Accession: VCV000029654.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37017508 (GRCh38) [ NCBI UCSC ] 3: 37058999 (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 Apr 12, 2013 Jun 17, 2024 Sep 5, 2013 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000249.4:c.793C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Arg265Cys missense NM_001167617.3:c.499C>T NP_001161089.1:p.Arg167Cys missense NM_001167618.3:c.70C>T NP_001161090.1:p.Arg24Cys missense NM_001167619.3:c.70C>T NP_001161091.1:p.Arg24Cys missense NM_001258271.2:c.793C>T NP_001245200.1:p.Arg265Cys missense NM_001258273.2:c.70C>T NP_001245202.1:p.Arg24Cys missense NM_001258274.3:c.70C>T NP_001245203.1:p.Arg24Cys missense NM_001354615.2:c.70C>T NP_001341544.1:p.Arg24Cys missense NM_001354616.2:c.70C>T NP_001341545.1:p.Arg24Cys missense NM_001354617.2:c.70C>T NP_001341546.1:p.Arg24Cys missense NM_001354618.2:c.70C>T NP_001341547.1:p.Arg24Cys missense NM_001354619.2:c.70C>T NP_001341548.1:p.Arg24Cys missense NM_001354620.2:c.499C>T NP_001341549.1:p.Arg167Cys missense NM_001354621.2:c.-139-2802C>T intron variant NM_001354622.2:c.-139-2802C>T intron variant NM_001354623.2:c.-139-2802C>T intron variant NM_001354624.2:c.-37+2964C>T intron variant NM_001354625.2:c.-37+2964C>T intron variant NM_001354626.2:c.-37+2964C>T intron variant NM_001354627.2:c.-37+2964C>T intron variant NM_001354628.2:c.793C>T NP_001341557.1:p.Arg265Cys missense NM_001354629.2:c.694C>T NP_001341558.1:p.Arg232Cys missense NM_001354630.2:c.793C>T NP_001341559.1:p.Arg265Cys missense NC_000003.12:g.37017508C>T NC_000003.11:g.37058999C>T NG_007109.2:g.29159C>T LRG_216:g.29159C>T LRG_216t1:c.793C>T LRG_216p1:p.Arg265Cys P40692:p.Arg265Cys uc010hgn.1:c.793C>T - Protein change
- R265C, R24C, R232C, R167C
- Other names
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- Canonical SPDI
- NC_000003.12:37017507:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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. |
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| MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5693 | 5754 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 19, 2023 | RCV000022502.39 | |
| Pathogenic (3) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075872.16 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 30, 2023 | RCV000034802.22 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2022 | RCV000220712.16 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2024 | RCV000524317.16 | |
| Pathogenic (2) |
no assertion criteria provided
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- | RCV001093673.10 | |
| Pathogenic (2) |
criteria provided, single submitter
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Feb 10, 2018 | RCV000677879.9 |
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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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106886.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
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Pathogenic
(Apr 21, 2016)
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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: SCV000696181.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and … (more)
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/4 in silico tools predict the variant to be disease causing (SNPs&GO was not capture due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project while it was observed in several HNPCC patients indicating pathogenicity. Moreover, the variant is considered to be a founder mutation in populations of Chinese/Taiwanese origin. Functional studies report the variant to result in exon skipping and a partial MMR defect which in combination likely result in a pathogenic impact. Furthermore, a clinical laboratory and databases cite variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic. (less)
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Pathogenic
(Feb 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
germline
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3DMed Clinical Laboratory Inc
Accession: SCV000804040.1
First in ClinVar: Aug 26, 2018 Last updated: Aug 26, 2018 |
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Pathogenic
(Nov 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731294.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, … (more)
The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, Ta ng 2009, InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.p hp). It segregated with disease in at least 12 family members (Hardt 2011, Tang 2009). Functional studies using patient mRNA showed that the variant leads to ex on skipping and protein truncation (Casey 2005). Additionally, this variant has been classified as pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT pa nel (ClinVar SCV000106886.2). In summary, this variant meets criteria to be clas sified as pathogenic for Lynch Syndrome in an autosomal dominant manner based up on segregation studies and the impact of the variant on the protein. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429381.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 22, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449582.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Mar 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677736.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(May 30, 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: SCV000279078.12
First in ClinVar: May 29, 2016 Last updated: Jun 10, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing and reduced mRNA and protein expression as well as deceased protein stability and reduced binding of … (more)
Published functional studies demonstrate a damaging effect: aberrant splicing and reduced mRNA and protein expression as well as deceased protein stability and reduced binding of MLH1 to PMS2 (Yuen et al., 2002; Casey et al., 2005; Perera et al., 2008; Perera et al., 2010; Andersen et al., 2012; Fan et al., 2012; Soukarieh et al., 2016); Observed in individuals with personal or family histories consistent with pathogenic variants in MLH1 and concordant tumor studies (Wahlberg et al., 1999; Hutter et al., 2002; Yuen et al., 2002; Hendriks et al., 2003; Mangold et al., 2005; Wolf et al., 2005; Lagerstedt Robinson et al., 2007; Berginc et al., 2009; Choi et al., 2009; Tang et al., 2009; Chang et al., 2010; Sjursen et al., 2010; Woods et al., 2010; Bonadona et al., 2011; Hardt et al., 2011; Fan et al., 2012; Liu et al., 2014; Guindalini et al., 2015; Win et al., 2015; Jiang W et al., 2019; Chang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17210669, 20020535, 18561205, 22824075, 20045164, 21404117, 20682701, 19224586, 21681552, 20864636, 28127413, 15731775, 21952876, 11781295, 11555625, 17594722, 22736432, 22949387, 22753075, 17135187, 23760103, 10495924, 16995940, 15849733, 12547705, 19698169, 26247049, 22843852, 24710284, 21642682, 16216036, 19526325, 20587412, 25345868, 17312306, 21155023, 26053027, 26248088, 17192056, 15926618, 12011148, 26202870, 23741719, 16830052, 15713769, 12386821, 17510385, 26761715, 25081409, 11948175, 28445943, 30274973, 31589614, 32849802, 31332305, 19419416, 18205192, 33260537, 29758216, 24362816, 31447099, 30787465, 30521064, 31830689) (less)
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009353.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely pathogenic
(Mar 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018207.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic … (more)
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jan 01, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684870.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 265 in the MutS interacting domain of the MLH1 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with cysteine at codon 265 in the MutS interacting domain of the MLH1 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). Functional studies have shown that this variant significantly decreases MLH1 protein stability (PMID: 18205192) and the ability of MLH1 protein to bind PMS2 (PMID: 21952876). This variant has also been shown to affect mRNA splicing (PMID: 12386821, 15713769, 18561205). This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 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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Ambry Genetics
Accession: SCV000276047.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R265C pathogenic mutation (also known as c.793C>T), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at … (more)
The p.R265C pathogenic mutation (also known as c.793C>T), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at nucleotide position 793. The arginine at codon 265 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in many individuals with early-onset colorectal cancer with concordant tumor results and family histories which meet Amsterdam criteria (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77; Woods MO et al. Gut. 2010 Oct;59:1369-77; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Ambry internal data). This mutation has been associated with exon-skipping, premature protein truncation, and low expression of the variant allele (Casey G et al. JAMA. 2005 Feb;293:799-809; Tournier I et al. Hum. Mut. 2008 Dec;29:1412-24; van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This mutation has also been shown to segregate with disease in several families meeting Amsterdam criteria (De Jong AE et al. Gastroenterology. 2004 Jan;126:42-8; Tang R et al. Clin. Genet. 2009 Apr;75:334-45; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004190609.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176523.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.793C>T(p.Arg265Cys) variant in MLH1 gene has been reported in heterozygous state in multiple individuals affected with colorectal cancer (Tang R, et. al., 2009; … (more)
The missense c.793C>T(p.Arg265Cys) variant in MLH1 gene has been reported in heterozygous state in multiple individuals affected with colorectal cancer (Tang R, et. al., 2009; Choi YH, et. al., 2009). This variant has been observed to segregate with disease (Tang R, et. al., 2009). Functional studies demonstrate skipping of exon 9-10, aberrant splicing, reduced mRNA and protein expression as well as deceased protein stability, hence proving a damaging effect (Fan Y, et. al., 2012; Casey G, et. al., 2005). The p.Arg265Cys variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg265Cys in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 265 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Neoplasm (present)
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Pathogenic
(Jan 09, 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: SCV000262499.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein (p.Arg265Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 11781295, 17135187, 17510385). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205, 22736432, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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variant of unknown significance
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043333.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 2
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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Ding PR Lab, Sun Yat-sen University Cancer Center
Accession: SCV001250854.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Observation 1:
Age: 50-59 years
Sex: female
Geographic origin: China
Observation 2:
Age: 50-59 years
Sex: female
Geographic origin: China
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
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: SCV000592378.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 13, 2021 |
Comment:
The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). … (more)
The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). In one study, this variant was reported in 2 different families and was associated with skipping of exons 9 and 10 from cDNA (Casey 2005). In another report, including probands who met Amsterdam criteria for HNPCC or who had a family history, this variant was found to reduce exon inclusion. This variant has been tested in different functional assays at the protein level, with results that were not always consistent; the p.Arg265Cys was associated with a mild reduction of mismatch repair efficiency in four studies (Plotz 2006; Ellison 2001; Wanat 2007; Takahashi 2007) but not in a fifth one (Trojan 2002) (Tournier 2007). One large study of Tawainese patients demonstrated that the p.Arg265Cys variant was identified in 13 out of 93 unrelated families. In total, 93 cancers were noted in these 13 families including 66 with cases of colon cancer, 6 cases of rectal cancer, 3 cases of endometrial cancer, 6 cases of gastric cancer, 1 case of ovarian cancer and 11 cases of other types of cancer (Tang 2009). In another report, deficient MLH1 IHC status and MSI-H tumor was noted in an individual with this variant who developed colorectal cancer at age 55 (Perera 2010). In summary, based on the above information this variant is classified as pathogenic. (less)
Number of individuals with the variant: 9
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959956.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964907.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Apr 01, 2009)
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no assertion criteria provided
Method: literature only
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LYNCH SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000043791.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
Comment on evidence:
In affected members of 13 Taiwanese families with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Tang et al. (2009) identified a heterozygous 793C-T transition in exon … (more)
In affected members of 13 Taiwanese families with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Tang et al. (2009) identified a heterozygous 793C-T transition in exon 10 of the MLH1 gene, resulting in an arg265-to-cys (R265C) substitution. The mutation was not found in 300 controls. Cancers that occurred included colon, rectal, gastric, endometrial, ovarian, breast, and others. Haplotype analysis indicated 2 common haplotypes, 1 of which was shared by 10 families, suggesting a common origin in China several centuries ago. (less)
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not provided
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no classification provided
Method: literature only
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002054063.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
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Comment:
Comment:
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/4 in silico tools predict the variant to be disease causing (SNPs&GO was not capture due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project while it was observed in several HNPCC patients indicating pathogenicity. Moreover, the variant is considered to be a founder mutation in populations of Chinese/Taiwanese origin. Functional studies report the variant to result in exon skipping and a partial MMR defect which in combination likely result in a pathogenic impact. Furthermore, a clinical laboratory and databases cite variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
Comment:
The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, Ta ng 2009, InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.p hp). It segregated with disease in at least 12 family members (Hardt 2011, Tang 2009). Functional studies using patient mRNA showed that the variant leads to ex on skipping and protein truncation (Casey 2005). Additionally, this variant has been classified as pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT pa nel (ClinVar SCV000106886.2). In summary, this variant meets criteria to be clas sified as pathogenic for Lynch Syndrome in an autosomal dominant manner based up on segregation studies and the impact of the variant on the protein.
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing and reduced mRNA and protein expression as well as deceased protein stability and reduced binding of MLH1 to PMS2 (Yuen et al., 2002; Casey et al., 2005; Perera et al., 2008; Perera et al., 2010; Andersen et al., 2012; Fan et al., 2012; Soukarieh et al., 2016); Observed in individuals with personal or family histories consistent with pathogenic variants in MLH1 and concordant tumor studies (Wahlberg et al., 1999; Hutter et al., 2002; Yuen et al., 2002; Hendriks et al., 2003; Mangold et al., 2005; Wolf et al., 2005; Lagerstedt Robinson et al., 2007; Berginc et al., 2009; Choi et al., 2009; Tang et al., 2009; Chang et al., 2010; Sjursen et al., 2010; Woods et al., 2010; Bonadona et al., 2011; Hardt et al., 2011; Fan et al., 2012; Liu et al., 2014; Guindalini et al., 2015; Win et al., 2015; Jiang W et al., 2019; Chang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17210669, 20020535, 18561205, 22824075, 20045164, 21404117, 20682701, 19224586, 21681552, 20864636, 28127413, 15731775, 21952876, 11781295, 11555625, 17594722, 22736432, 22949387, 22753075, 17135187, 23760103, 10495924, 16995940, 15849733, 12547705, 19698169, 26247049, 22843852, 24710284, 21642682, 16216036, 19526325, 20587412, 25345868, 17312306, 21155023, 26053027, 26248088, 17192056, 15926618, 12011148, 26202870, 23741719, 16830052, 15713769, 12386821, 17510385, 26761715, 25081409, 11948175, 28445943, 30274973, 31589614, 32849802, 31332305, 19419416, 18205192, 33260537, 29758216, 24362816, 31447099, 30787465, 30521064, 31830689)
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
This missense variant replaces arginine with cysteine at codon 265 in the MutS interacting domain of the MLH1 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). Functional studies have shown that this variant significantly decreases MLH1 protein stability (PMID: 18205192) and the ability of MLH1 protein to bind PMS2 (PMID: 21952876). This variant has also been shown to affect mRNA splicing (PMID: 12386821, 15713769, 18561205). This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.R265C pathogenic mutation (also known as c.793C>T), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at nucleotide position 793. The arginine at codon 265 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in many individuals with early-onset colorectal cancer with concordant tumor results and family histories which meet Amsterdam criteria (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77; Woods MO et al. Gut. 2010 Oct;59:1369-77; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Ambry internal data). This mutation has been associated with exon-skipping, premature protein truncation, and low expression of the variant allele (Casey G et al. JAMA. 2005 Feb;293:799-809; Tournier I et al. Hum. Mut. 2008 Dec;29:1412-24; van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This mutation has also been shown to segregate with disease in several families meeting Amsterdam criteria (De Jong AE et al. Gastroenterology. 2004 Jan;126:42-8; Tang R et al. Clin. Genet. 2009 Apr;75:334-45; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The missense c.793C>T(p.Arg265Cys) variant in MLH1 gene has been reported in heterozygous state in multiple individuals affected with colorectal cancer (Tang R, et. al., 2009; Choi YH, et. al., 2009). This variant has been observed to segregate with disease (Tang R, et. al., 2009). Functional studies demonstrate skipping of exon 9-10, aberrant splicing, reduced mRNA and protein expression as well as deceased protein stability, hence proving a damaging effect (Fan Y, et. al., 2012; Casey G, et. al., 2005). The p.Arg265Cys variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg265Cys in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 265 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein (p.Arg265Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 11781295, 17135187, 17510385). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205, 22736432, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission to Uncertain significance.
Comment:
The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). In one study, this variant was reported in 2 different families and was associated with skipping of exons 9 and 10 from cDNA (Casey 2005). In another report, including probands who met Amsterdam criteria for HNPCC or who had a family history, this variant was found to reduce exon inclusion. This variant has been tested in different functional assays at the protein level, with results that were not always consistent; the p.Arg265Cys was associated with a mild reduction of mismatch repair efficiency in four studies (Plotz 2006; Ellison 2001; Wanat 2007; Takahashi 2007) but not in a fifth one (Trojan 2002) (Tournier 2007). One large study of Tawainese patients demonstrated that the p.Arg265Cys variant was identified in 13 out of 93 unrelated families. In total, 93 cancers were noted in these 13 families including 66 with cases of colon cancer, 6 cases of rectal cancer, 3 cases of endometrial cancer, 6 cases of gastric cancer, 1 case of ovarian cancer and 11 cases of other types of cancer (Tang 2009). In another report, deficient MLH1 IHC status and MSI-H tumor was noted in an individual with this variant who developed colorectal cancer at age 55 (Perera 2010). In summary, based on the above information this variant is classified as pathogenic.
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:
Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
Comment:
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/4 in silico tools predict the variant to be disease causing (SNPs&GO was not capture due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project while it was observed in several HNPCC patients indicating pathogenicity. Moreover, the variant is considered to be a founder mutation in populations of Chinese/Taiwanese origin. Functional studies report the variant to result in exon skipping and a partial MMR defect which in combination likely result in a pathogenic impact. Furthermore, a clinical laboratory and databases cite variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
Comment:
The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, Ta ng 2009, InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.p hp). It segregated with disease in at least 12 family members (Hardt 2011, Tang 2009). Functional studies using patient mRNA showed that the variant leads to ex on skipping and protein truncation (Casey 2005). Additionally, this variant has been classified as pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT pa nel (ClinVar SCV000106886.2). In summary, this variant meets criteria to be clas sified as pathogenic for Lynch Syndrome in an autosomal dominant manner based up on segregation studies and the impact of the variant on the protein.
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing and reduced mRNA and protein expression as well as deceased protein stability and reduced binding of MLH1 to PMS2 (Yuen et al., 2002; Casey et al., 2005; Perera et al., 2008; Perera et al., 2010; Andersen et al., 2012; Fan et al., 2012; Soukarieh et al., 2016); Observed in individuals with personal or family histories consistent with pathogenic variants in MLH1 and concordant tumor studies (Wahlberg et al., 1999; Hutter et al., 2002; Yuen et al., 2002; Hendriks et al., 2003; Mangold et al., 2005; Wolf et al., 2005; Lagerstedt Robinson et al., 2007; Berginc et al., 2009; Choi et al., 2009; Tang et al., 2009; Chang et al., 2010; Sjursen et al., 2010; Woods et al., 2010; Bonadona et al., 2011; Hardt et al., 2011; Fan et al., 2012; Liu et al., 2014; Guindalini et al., 2015; Win et al., 2015; Jiang W et al., 2019; Chang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17210669, 20020535, 18561205, 22824075, 20045164, 21404117, 20682701, 19224586, 21681552, 20864636, 28127413, 15731775, 21952876, 11781295, 11555625, 17594722, 22736432, 22949387, 22753075, 17135187, 23760103, 10495924, 16995940, 15849733, 12547705, 19698169, 26247049, 22843852, 24710284, 21642682, 16216036, 19526325, 20587412, 25345868, 17312306, 21155023, 26053027, 26248088, 17192056, 15926618, 12011148, 26202870, 23741719, 16830052, 15713769, 12386821, 17510385, 26761715, 25081409, 11948175, 28445943, 30274973, 31589614, 32849802, 31332305, 19419416, 18205192, 33260537, 29758216, 24362816, 31447099, 30787465, 30521064, 31830689)
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
This missense variant replaces arginine with cysteine at codon 265 in the MutS interacting domain of the MLH1 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). Functional studies have shown that this variant significantly decreases MLH1 protein stability (PMID: 18205192) and the ability of MLH1 protein to bind PMS2 (PMID: 21952876). This variant has also been shown to affect mRNA splicing (PMID: 12386821, 15713769, 18561205). This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.R265C pathogenic mutation (also known as c.793C>T), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at nucleotide position 793. The arginine at codon 265 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in many individuals with early-onset colorectal cancer with concordant tumor results and family histories which meet Amsterdam criteria (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77; Woods MO et al. Gut. 2010 Oct;59:1369-77; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Ambry internal data). This mutation has been associated with exon-skipping, premature protein truncation, and low expression of the variant allele (Casey G et al. JAMA. 2005 Feb;293:799-809; Tournier I et al. Hum. Mut. 2008 Dec;29:1412-24; van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This mutation has also been shown to segregate with disease in several families meeting Amsterdam criteria (De Jong AE et al. Gastroenterology. 2004 Jan;126:42-8; Tang R et al. Clin. Genet. 2009 Apr;75:334-45; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The missense c.793C>T(p.Arg265Cys) variant in MLH1 gene has been reported in heterozygous state in multiple individuals affected with colorectal cancer (Tang R, et. al., 2009; Choi YH, et. al., 2009). This variant has been observed to segregate with disease (Tang R, et. al., 2009). Functional studies demonstrate skipping of exon 9-10, aberrant splicing, reduced mRNA and protein expression as well as deceased protein stability, hence proving a damaging effect (Fan Y, et. al., 2012; Casey G, et. al., 2005). The p.Arg265Cys variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg265Cys in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 265 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein (p.Arg265Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 11781295, 17135187, 17510385). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205, 22736432, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission to Uncertain significance.
Comment:
The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). In one study, this variant was reported in 2 different families and was associated with skipping of exons 9 and 10 from cDNA (Casey 2005). In another report, including probands who met Amsterdam criteria for HNPCC or who had a family history, this variant was found to reduce exon inclusion. This variant has been tested in different functional assays at the protein level, with results that were not always consistent; the p.Arg265Cys was associated with a mild reduction of mismatch repair efficiency in four studies (Plotz 2006; Ellison 2001; Wanat 2007; Takahashi 2007) but not in a fifth one (Trojan 2002) (Tournier 2007). One large study of Tawainese patients demonstrated that the p.Arg265Cys variant was identified in 13 out of 93 unrelated families. In total, 93 cancers were noted in these 13 families including 66 with cases of colon cancer, 6 cases of rectal cancer, 3 cases of endometrial cancer, 6 cases of gastric cancer, 1 case of ovarian cancer and 11 cases of other types of cancer (Tang 2009). In another report, deficient MLH1 IHC status and MSI-H tumor was noted in an individual with this variant who developed colorectal cancer at age 55 (Perera 2010). In summary, based on the above information this variant is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
| Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. | Abildgaard AB | eLife | 2019 | PMID: 31697235 |
| A molecular inversion probe-based next-generation sequencing panel to detect germline mutations in Chinese early-onset colorectal cancer patients. | Zhang J | Oncotarget | 2017 | PMID: 28445943 |
| Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. | van der Klift HM | Molecular genetics & genomic medicine | 2015 | PMID: 26247049 |
| 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 |
| 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 |
| A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
| Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. | Andersen SD | Human mutation | 2012 | PMID: 22753075 |
| Comprehensive functional assessment of MLH1 variants of unknown significance. | Borràs E | Human mutation | 2012 | PMID: 22736432 |
| Influence of eight unclassified missense variants of the MLH1 gene on Lynch syndrome susceptibility. | Fan Y | Biochemical genetics | 2012 | PMID: 21952876 |
| Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
| A novel and rapid method of determining the effect of unclassified MLH1 genetic variants on differential allelic expression. | Perera S | The Journal of molecular diagnostics : JMD | 2010 | PMID: 20864636 |
| The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. | Woods MO | Gut | 2010 | PMID: 20682701 |
| Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. | Sjursen W | Journal of medical genetics | 2010 | PMID: 20587412 |
| A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. | Drost M | Human mutation | 2010 | PMID: 20020535 |
| Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. | Choi YH | Hereditary cancer in clinical practice | 2009 | PMID: 19698169 |
| Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. | Tang R | Clinical genetics | 2009 | PMID: 19419416 |
| A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. | Tournier I | Human mutation | 2008 | PMID: 18561205 |
| The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation. | Perera S | Human mutation | 2008 | PMID: 18205192 |
| Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
| Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. | Lagerstedt Robinson K | Journal of the National Cancer Institute | 2007 | PMID: 17312306 |
| The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. | Wanat JJ | Human molecular genetics | 2007 | PMID: 17210669 |
| Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair. | Plotz G | Nucleic acids research | 2006 | PMID: 17135187 |
| In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. | Lastella P | BMC genomics | 2006 | PMID: 16995940 |
| Spectrum of germ-line MLH1 and MSH2 mutations in Austrian patients with hereditary nonpolyposis colorectal cancer. | Wolf B | Wiener klinische Wochenschrift | 2005 | PMID: 15926618 |
| Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
| Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer. | Halvarsson B | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2005 | PMID: 15731775 |
| Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
| The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. | De Jong AE | Gastroenterology | 2004 | PMID: 14699485 |
| Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. | Hendriks Y | The American journal of pathology | 2003 | PMID: 12547705 |
| Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. | Yuen ST | Oncogene | 2002 | PMID: 12386821 |
| Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha. | Räschle M | The Journal of biological chemistry | 2002 | PMID: 11948175 |
| Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. | Trojan J | Gastroenterology | 2002 | PMID: 11781295 |
| Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. | Ellison AR | Human molecular genetics | 2001 | PMID: 11555625 |
| Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1. | Wahlberg S | Genetic testing | 1999 | PMID: 10495924 |
| http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.793C%3ET | - | - | - | - |
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Text-mined citations for rs63751194 ...
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Record last updated Nov 10, 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.