ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1942C>T (p.Pro648Ser)
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_000249.4(MLH1):c.1942C>T (p.Pro648Ser)
Variation ID: 17097 Accession: VCV000017097.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37048562 (GRCh38) [ NCBI UCSC ] 3: 37090053 (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 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1942C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Pro648Ser missense NM_001167617.3:c.1648C>T NP_001161089.1:p.Pro550Ser missense NM_001167618.3:c.1219C>T NP_001161090.1:p.Pro407Ser missense NM_001167619.3:c.1219C>T NP_001161091.1:p.Pro407Ser missense NM_001258271.2:c.1896+879C>T intron variant NM_001258273.2:c.1219C>T NP_001245202.1:p.Pro407Ser missense NM_001258274.3:c.1219C>T NP_001245203.1:p.Pro407Ser missense NM_001354615.2:c.1219C>T NP_001341544.1:p.Pro407Ser missense NM_001354616.2:c.1219C>T NP_001341545.1:p.Pro407Ser missense NM_001354617.2:c.1219C>T NP_001341546.1:p.Pro407Ser missense NM_001354618.2:c.1219C>T NP_001341547.1:p.Pro407Ser missense NM_001354619.2:c.1219C>T NP_001341548.1:p.Pro407Ser missense NM_001354620.2:c.1648C>T NP_001341549.1:p.Pro550Ser missense NM_001354621.2:c.919C>T NP_001341550.1:p.Pro307Ser missense NM_001354622.2:c.919C>T NP_001341551.1:p.Pro307Ser missense NM_001354623.2:c.919C>T NP_001341552.1:p.Pro307Ser missense NM_001354624.2:c.868C>T NP_001341553.1:p.Pro290Ser missense NM_001354625.2:c.868C>T NP_001341554.1:p.Pro290Ser missense NM_001354626.2:c.868C>T NP_001341555.1:p.Pro290Ser missense NM_001354627.2:c.868C>T NP_001341556.1:p.Pro290Ser missense NM_001354628.2:c.1897-342C>T intron variant NM_001354629.2:c.1843C>T NP_001341558.1:p.Pro615Ser missense NM_001354630.2:c.1777C>T NP_001341559.1:p.Pro593Ser missense NC_000003.12:g.37048562C>T NC_000003.11:g.37090053C>T NG_007109.2:g.60213C>T LRG_216:g.60213C>T LRG_216t1:c.1942C>T LRG_216p1:p.Pro648Ser P40692:p.Pro648Ser - Protein change
- P648S, P307S, P407S, P290S, P615S, P550S, P593S
- Other names
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- Canonical SPDI
- NC_000003.12:37048561: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
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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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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5624 | 5679 |
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
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
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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) |
criteria provided, single submitter
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Mar 28, 2018 | RCV000162472.6 | |
Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075432.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV001040524.3 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2004 | RCV001267884.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2019 | RCV001284501.1 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 24, 2023 | RCV000018629.29 |
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
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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
(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: SCV000106428.3
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:
Multifactorial likelihood analysis posterior probability >0.99
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Pathogenic
(Dec 27, 2019)
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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: SCV001470330.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. … (more)
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals (less)
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Pathogenic
(Nov 21, 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: SCV001204103.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 648 of the MLH1 protein (p.Pro648Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 648 of the MLH1 protein (p.Pro648Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch Syndrome (PMID: 12112654, 15139004, 16724012). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17097). 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 MLH1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15139004, 16724012, 21404117). This variant disrupts the p.Pro648 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11726306, 16083711, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jul 24, 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: SCV004188465.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 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: 27363726]. (less)
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Pathogenic
(Mar 28, 2018)
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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: SCV000212839.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.P648S pathogenic mutation (also known as c.1942C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at … (more)
The p.P648S pathogenic mutation (also known as c.1942C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1942. The proline at codon 648 is replaced by serine, an amino acid with similar properties. This mutation has been reported in multiple individuals satisfying clinical diagnostic criteria for HNPCC/Lynch syndrome (Bisgaard et al. Hum Mut 2002 Jul; 20(1): 20-7; Raevaara et al. Genes Chromosomes Cancer 2004 Jul; 40(3): 261-5; Belvederesi et al. Eur J Hum Genet 2006 Jul; 14(7): 853 9; Ou et al. Hum Mut 2007 Nov; 28(11): 104754). Tumor studies in some of these individuals demonstrated microsatellite instability and loss of MLH1 protein expression on immunohistochemistry. In addition, this mutation has been shown to disrupt interaction between MLH1 and PMS2 in vitro (Belvederesi et al. Eur J Hum Genet 2006 Jul; 14(7): 853-9). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; 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
(Jul 01, 2004)
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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: SCV000038912.8
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
Comment on evidence:
In 8 affected members of the Danish family with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) reported by Bisgaard et al. (2002), Raevaara et al. (2004) … (more)
In 8 affected members of the Danish family with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) reported by Bisgaard et al. (2002), Raevaara et al. (2004) identified a pro648-to-ser (P648S) mutation in the MLH1 gene. Only 1 member, a 6-year-old child with first-cousin parents, was homozygous for the mutation. She had mild features of type I neurofibromatosis (NF1; 162200) and no hematologic cancers. She displayed cafe-au-lait spots and a skin tumor clinically diagnosed as a neurofibroma, but no axillary freckles or other abnormalities. The phenotype was consistent with the spectrum of mismatch repair cancer syndrome (MMRCS1; 276300). Raevaara et al. (2004) commented that the mutated protein was unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual were linked to shortage of the functional protein. (less)
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Pathogenic
(Jul 01, 2004)
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no assertion criteria provided
Method: literature only
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MISMATCH REPAIR CANCER SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001446363.2
First in ClinVar: Nov 28, 2020 Last updated: Nov 19, 2022 |
Comment on evidence:
In 8 affected members of the Danish family with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) reported by Bisgaard et al. (2002), Raevaara et al. (2004) … (more)
In 8 affected members of the Danish family with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) reported by Bisgaard et al. (2002), Raevaara et al. (2004) identified a pro648-to-ser (P648S) mutation in the MLH1 gene. Only 1 member, a 6-year-old child with first-cousin parents, was homozygous for the mutation. She had mild features of type I neurofibromatosis (NF1; 162200) and no hematologic cancers. She displayed cafe-au-lait spots and a skin tumor clinically diagnosed as a neurofibroma, but no axillary freckles or other abnormalities. The phenotype was consistent with the spectrum of mismatch repair cancer syndrome (MMRCS1; 276300). Raevaara et al. (2004) commented that the mutated protein was unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual were linked to shortage of the functional protein. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. | Jiang W | International journal of cancer | 2019 | PMID: 30521064 |
Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. | Morris B | BMC genetics | 2016 | PMID: 27363726 |
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 |
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with clinical, genetic and functional features. | Belvederesi L | European journal of human genetics : EJHG | 2006 | PMID: 16724012 |
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. | Raevaara TE | Gastroenterology | 2005 | PMID: 16083711 |
HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. | Raevaara TE | Genes, chromosomes & cancer | 2004 | PMID: 15139004 |
Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. | Bisgaard ML | Human mutation | 2002 | PMID: 12112654 |
Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms? | Müller-Koch Y | European journal of medical research | 2001 | PMID: 11726306 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1942C%3ET | - | - | - | - |
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Text-mined citations for rs63750899 ...
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.