ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1808C>G (p.Pro603Arg)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1808C>G (p.Pro603Arg)
Variation ID: 41636 Accession: VCV000041636.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047595 (GRCh38) [ NCBI UCSC ] 3: 37089086 (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 Oct 8, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1808C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Pro603Arg missense NM_001167617.3:c.1514C>G NP_001161089.1:p.Pro505Arg missense NM_001167618.3:c.1085C>G NP_001161090.1:p.Pro362Arg missense NM_001167619.3:c.1085C>G NP_001161091.1:p.Pro362Arg missense NM_001258271.2:c.1808C>G NP_001245200.1:p.Pro603Arg missense NM_001258273.2:c.1085C>G NP_001245202.1:p.Pro362Arg missense NM_001258274.3:c.1085C>G NP_001245203.1:p.Pro362Arg missense NM_001354615.2:c.1085C>G NP_001341544.1:p.Pro362Arg missense NM_001354616.2:c.1085C>G NP_001341545.1:p.Pro362Arg missense NM_001354617.2:c.1085C>G NP_001341546.1:p.Pro362Arg missense NM_001354618.2:c.1085C>G NP_001341547.1:p.Pro362Arg missense NM_001354619.2:c.1085C>G NP_001341548.1:p.Pro362Arg missense NM_001354620.2:c.1514C>G NP_001341549.1:p.Pro505Arg missense NM_001354621.2:c.785C>G NP_001341550.1:p.Pro262Arg missense NM_001354622.2:c.785C>G NP_001341551.1:p.Pro262Arg missense NM_001354623.2:c.785C>G NP_001341552.1:p.Pro262Arg missense NM_001354624.2:c.734C>G NP_001341553.1:p.Pro245Arg missense NM_001354625.2:c.734C>G NP_001341554.1:p.Pro245Arg missense NM_001354626.2:c.734C>G NP_001341555.1:p.Pro245Arg missense NM_001354627.2:c.734C>G NP_001341556.1:p.Pro245Arg missense NM_001354628.2:c.1808C>G NP_001341557.1:p.Pro603Arg missense NM_001354629.2:c.1709C>G NP_001341558.1:p.Pro570Arg missense NM_001354630.2:c.1732-922C>G intron variant NC_000003.12:g.37047595C>G NC_000003.11:g.37089086C>G NG_007109.2:g.59246C>G LRG_216:g.59246C>G LRG_216t1:c.1808C>G LRG_216p1:p.Pro603Arg P40692:p.Pro603Arg - Protein change
- P603R, P245R, P362R, P505R, P570R, P262R
- Other names
- p.P603R:CCC>CGC
- Canonical SPDI
- NC_000003.12:37047594:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
5689 | 5749 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2024 | RCV000034541.22 | |
Likely benign (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075369.9 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2024 | RCV000130908.14 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000417382.17 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001082925.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV000987184.10 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001356052.4 | |
MLH1-related disorder
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Likely benign (1) |
no assertion criteria provided
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Apr 9, 2019 | RCV003891466.2 |
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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Likely benign
(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: SCV000106364.3
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 0.001-0.049
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Likely benign
(Mar 07, 2015)
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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: SCV000537430.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
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Benign
(Jul 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889389.4
First in ClinVar: Apr 12, 2013 Last updated: Jan 06, 2024 |
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Likely benign
(Dec 19, 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: SCV000185817.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Mar 22, 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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045484.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001136423.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 28, 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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001310414.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Jul 15, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002528678.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jul 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033982.10
First in ClinVar: Sep 16, 2023 Last updated: Oct 08, 2024 |
Comment:
MLH1: PP3, BS3
Number of individuals with the variant: 4
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Likely benign
(Mar 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211144.6
First in ClinVar: Feb 24, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 11726306, 17510385, 21404117, 23047549, 23741719, 19117025, 22736432, 24362816, 22949387, 22703879, 25871441, 18561205, 22290698, 31784484)
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Benign
(Oct 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919654.2
First in ClinVar: May 31, 2019 Last updated: Nov 20, 2021 |
Comment:
Variant summary: MLH1 c.1808C>G (p.Pro603Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the … (more)
Variant summary: MLH1 c.1808C>G (p.Pro603Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251344 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00016 vs 0.00071), allowing no conclusion about variant significance. However, it is predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.0028 (28/10076). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. c.1808C>G has been reported in the literature in individuals affected with a variety of cancers such as Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome, epithelial ovarian cancer (example, Hardt_2011, Tournier_2008, Pal_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (MLH1 complete gene deletion), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function (example, Takahashi_2007, Drost_2018). The most pronounced variant effect results in 82.5% normal mismatch repair (MMR) activity (Takahashi_2007), while a subsequent study reports 97% of normal mismatch repair (MMR) activity (Drost_2018). Furthermore, binding partner interaction as determined by Y2H assays is +, Nuclear localization as determined by transfections of fluorescently tagged proteins combined with microscopy is + (Drost_2018). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a predominant consensus as likely benign/benign (n=7) (VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Jul 07, 2023)
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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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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015884.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Likely benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760293.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Benign
(Jan 31, 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: SCV000218694.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
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: SCV001551110.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MLH1 p.Pro603Arg variant was identified in 6 of 4996 proband chromosomes (frequency: 0.005) from individuals or families with lynch syndrome and ovarian cancer (Pal … (more)
The MLH1 p.Pro603Arg variant was identified in 6 of 4996 proband chromosomes (frequency: 0.005) from individuals or families with lynch syndrome and ovarian cancer (Pal 2012, South 2009, Hardt 2011, Borras 2012, Tournier 2008). The variant was identified in dbSNP (rs63750876) as “with uncertain significance allele”, ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Integrated Genetics, Color and 2 other submitters, uncertain significance by Prevention Genetics and NIH and benign by Invitae and Quest Diagnostics) and UMD-LSDB (observed 4x). The variant was identified in control databases in 44 of 282,716 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 29 of 10,366 chromosomes (freq: 0.003 increasing the likelihood this could be a low frequency benign variant), Other in 5 of 7218 chromosomes (freq: 0.0007), European in 8 of 129,068 chromosomes (freq: 0.00006), Latino in 2 of 35,438 chromosomes (freq: 0.00006), while the variant was not observed in the African, East Asian, Finnish, and South Asian populations. Expression of the variant in yeast and human cells had no demonstrated effect on MLH1 protein levels, MMR activity and splicing (Norras 2012, Hardt 2011, Tournier 2008, Takahashi 2007). The p.Pro603 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (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: SCV000043326.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
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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Likely benign
(Apr 09, 2019)
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no assertion criteria provided
Method: clinical testing
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MLH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805956.4
First in ClinVar: Apr 12, 2013 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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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A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome. | Drost M | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30504929 |
Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization. | van der Velde KJ | Human mutation | 2015 | PMID: 25871441 |
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. | Pal T | British journal of cancer | 2012 | PMID: 23047549 |
Comprehensive functional assessment of MLH1 variants of unknown significance. | Borràs E | Human mutation | 2012 | PMID: 22736432 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers. | South SA | Cancer | 2009 | PMID: 19117025 |
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 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
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.1808C%3EG | - | - | - | - |
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Text-mined citations for rs63750876 ...
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.