ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1856C>A (p.Ala619Asp)
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.1856C>A (p.Ala619Asp)
Variation ID: 455408 Accession: VCV000455408.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047643 (GRCh38) [ NCBI UCSC ] 3: 37089134 (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 Dec 26, 2017 May 1, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1856C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Ala619Asp missense NM_001167617.3:c.1562C>A NP_001161089.1:p.Ala521Asp missense NM_001167618.3:c.1133C>A NP_001161090.1:p.Ala378Asp missense NM_001167619.3:c.1133C>A NP_001161091.1:p.Ala378Asp missense NM_001258271.2:c.1856C>A NP_001245200.1:p.Ala619Asp missense NM_001258273.2:c.1133C>A NP_001245202.1:p.Ala378Asp missense NM_001258274.3:c.1133C>A NP_001245203.1:p.Ala378Asp missense NM_001354615.2:c.1133C>A NP_001341544.1:p.Ala378Asp missense NM_001354616.2:c.1133C>A NP_001341545.1:p.Ala378Asp missense NM_001354617.2:c.1133C>A NP_001341546.1:p.Ala378Asp missense NM_001354618.2:c.1133C>A NP_001341547.1:p.Ala378Asp missense NM_001354619.2:c.1133C>A NP_001341548.1:p.Ala378Asp missense NM_001354620.2:c.1562C>A NP_001341549.1:p.Ala521Asp missense NM_001354621.2:c.833C>A NP_001341550.1:p.Ala278Asp missense NM_001354622.2:c.833C>A NP_001341551.1:p.Ala278Asp missense NM_001354623.2:c.833C>A NP_001341552.1:p.Ala278Asp missense NM_001354624.2:c.782C>A NP_001341553.1:p.Ala261Asp missense NM_001354625.2:c.782C>A NP_001341554.1:p.Ala261Asp missense NM_001354626.2:c.782C>A NP_001341555.1:p.Ala261Asp missense NM_001354627.2:c.782C>A NP_001341556.1:p.Ala261Asp missense NM_001354628.2:c.1856C>A NP_001341557.1:p.Ala619Asp missense NM_001354629.2:c.1757C>A NP_001341558.1:p.Ala586Asp missense NM_001354630.2:c.1732-874C>A intron variant NC_000003.12:g.37047643C>A NC_000003.11:g.37089134C>A NG_007109.2:g.59294C>A LRG_216:g.59294C>A LRG_216t1:c.1856C>A LRG_216p1:p.Ala619Asp - Protein change
- A619D, A521D, A261D, A278D, A378D, A586D
- Other names
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- Canonical SPDI
- NC_000003.12:37047642:C:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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
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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 |
5689 | 5749 |
Conditions - Germline
Condition
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 29, 2023 | RCV000528811.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2022 | RCV002258943.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Feb 03, 2022)
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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: SCV002528689.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MLH1 c.1856C>A (p.A619D) variant has not been reported in the literature in individuals with MLH1-related disease. It was observed in 1/113686 chromosomes of the … (more)
The MLH1 c.1856C>A (p.A619D) variant has not been reported in the literature in individuals with MLH1-related disease. It was observed in 1/113686 chromosomes of the European (non-Finnish) subpopulation, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 455408). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Dec 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000625104.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 619 of the MLH1 protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 619 of the MLH1 protein (p.Ala619Asp). This variant is present in population databases (rs747708787, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 455408). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. This variant disrupts the p.Ala619 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612827, 18561205, 21404117, 21520333, 23729658, 28514183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 07, 2020)
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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: SCV002718023.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A619D variant (also known as c.1856C>A), located in coding exon 16 of the MLH1 gene, results from a C to A substitution at nucleotide … (more)
The p.A619D variant (also known as c.1856C>A), located in coding exon 16 of the MLH1 gene, results from a C to A substitution at nucleotide position 1856. The alanine at codon 619 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. | Grandval P | Database : the journal of biological databases and curation | 2013 | PMID: 23729658 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
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 |
UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. | Béroud C | Human mutation | 2000 | PMID: 10612827 |
Text-mined citations for rs747708787 ...
HelpRecord last updated Sep 29, 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.