ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1616C>A (p.Ala539Asp)
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.
Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000249.4(MLH1):c.1616C>A (p.Ala539Asp)
Variation ID: 1343456 Accession: VCV001343456.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 37040243 (GRCh38) [ NCBI UCSC ] 3: 37081734 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 12, 2022 May 1, 2024 Jul 21, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000249.4:c.1616C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Ala539Asp missense NM_001167617.3:c.1322C>A NP_001161089.1:p.Ala441Asp missense NM_001167618.3:c.893C>A NP_001161090.1:p.Ala298Asp missense NM_001167619.3:c.893C>A NP_001161091.1:p.Ala298Asp missense NM_001258271.2:c.1616C>A NP_001245200.1:p.Ala539Asp missense NM_001258273.2:c.893C>A NP_001245202.1:p.Ala298Asp missense NM_001258274.3:c.893C>A NP_001245203.1:p.Ala298Asp missense NM_001354615.2:c.893C>A NP_001341544.1:p.Ala298Asp missense NM_001354616.2:c.893C>A NP_001341545.1:p.Ala298Asp missense NM_001354617.2:c.893C>A NP_001341546.1:p.Ala298Asp missense NM_001354618.2:c.893C>A NP_001341547.1:p.Ala298Asp missense NM_001354619.2:c.893C>A NP_001341548.1:p.Ala298Asp missense NM_001354620.2:c.1322C>A NP_001341549.1:p.Ala441Asp missense NM_001354621.2:c.593C>A NP_001341550.1:p.Ala198Asp missense NM_001354622.2:c.593C>A NP_001341551.1:p.Ala198Asp missense NM_001354623.2:c.593C>A NP_001341552.1:p.Ala198Asp missense NM_001354624.2:c.542C>A NP_001341553.1:p.Ala181Asp missense NM_001354625.2:c.542C>A NP_001341554.1:p.Ala181Asp missense NM_001354626.2:c.542C>A NP_001341555.1:p.Ala181Asp missense NM_001354627.2:c.542C>A NP_001341556.1:p.Ala181Asp missense NM_001354628.2:c.1616C>A NP_001341557.1:p.Ala539Asp missense NM_001354629.2:c.1517C>A NP_001341558.1:p.Ala506Asp missense NM_001354630.2:c.1616C>A NP_001341559.1:p.Ala539Asp missense NC_000003.12:g.37040243C>A NC_000003.11:g.37081734C>A NG_007109.2:g.51894C>A LRG_216:g.51894C>A LRG_216t1:c.1616C>A LRG_216p1:p.Ala539Asp P40692:p.Ala539Asp - Protein change
- A539D, A181D, A198D, A441D, A506D, A298D
- Other names
- -
- Canonical SPDI
- NC_000003.12:37040242:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5632 | 5687 |
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 27, 2022 | RCV001844474.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 20, 2022 | RCV002397764.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 25, 2022 | RCV002545235.2 | |
MLH1-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 27, 2023 | RCV003416490.4 |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 21, 2023 | RCV003451969.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Feb 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103416.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: MLH1 c.1616C>A (p.Ala539Asp) 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.1616C>A (p.Ala539Asp) 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 was absent in 251320 control chromosomes. c.1616C>A has been reported in the literature as segregating with colorectal cancer in two affected gene carriers from one family and has subsequently been cited by others (example, Parc_2003, Bonadona_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bouvet_2019). The most pronounced variant effect results in classification as pathogenic based on a methylation tolerance based functional assay. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
Likely pathogenic
(Mar 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MLH1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004107910.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MLH1 c.1616C>A variant is predicted to result in the amino acid substitution p.Ala539Asp. This variant has been reported in individuals with a personal and/or … (more)
The MLH1 c.1616C>A variant is predicted to result in the amino acid substitution p.Ala539Asp. This variant has been reported in individuals with a personal and/or family history of non-polyposis colorectal cancer (Table S3, Parc et al. 2003. PubMed ID: 12624141; eTable 1, Bonadona et al. 2011. PubMed ID: 21642682; Table S2, Bouvet et al. 2019. PubMed ID: 30998989). This variant has been reported to segregate with MLH1-associated tumors in a multigenerational kindred (Internal Data, Prevention Genetics LCC). The proband's tumor displayed complete loss of MLH1 and PMS2 expression by immunohistochemistry (Internal Data, Prevention Genetics LCC). In vitro experimental studies using a methylation tolerance assay suggest this variant impacts protein function (Table S2, Bouvet et al. 2019. PubMed ID: 30998989). Additional experimental studies using RT-PCR analysis suggest this variant does not impact pre-mRNA splicing (Table 1, Tournier et al. 2008. PubMed ID: 18561205). In silico analyses predict this variant to be pathogenic (Table 3, Ali et al. 2012. PubMed ID: 22290698). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1343456/). This variant is interpreted as likely pathogenic. (less)
|
|
Likely pathogenic
(Jul 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188511.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30998989, Myriad internal data]. This variant is expected to disrupt … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30998989, Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
|
|
Likely pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003525105.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 30998989). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 21642682; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 539 of the MLH1 protein (p.Ala539Asp). (less)
|
|
Likely pathogenic
(Sep 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002707985.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A539D variant (also known as c.1616C>A), located in coding exon 14 of the MLH1 gene, results from a C to A substitution at nucleotide … (more)
The p.A539D variant (also known as c.1616C>A), located in coding exon 14 of the MLH1 gene, results from a C to A substitution at nucleotide position 1616. The alanine at codon 539 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant was identified in the germline along with a somatic likely pathogenic MLH1 variant in an individual that met Amsterdam II criteria for Lynch syndrome and tumor displayed high microsatellite instability (MSI-H) with loss of both MLH1/PMS2 on immunohistochemistry (IHC) (Ambry internal data). Furthermore, this variant co-segregated with disease in three other affected family members (Ambry internal data). This variant was first reported in a French individual with colorectal cancer who satisfied at least one of the modified Amsterdam criteria and co-segregation with disease occurred in two affected carriers from this family (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13). This variant was also reported in three French families suspected of having Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This alteration had no effect on splicing in a minigene assay performed on HeLa cells (Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be inconclusive by in silico analyses. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
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 |
---|---|---|---|---|
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
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 |
Cancer risk in 348 French MSH2 or MLH1 gene carriers. | Parc Y | Journal of medical genetics | 2003 | PMID: 12624141 |
Text-mined citations for rs267607843 ...
HelpRecord last updated May 19, 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.