This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1682A>G (p.Tyr561Cys)
Germline
Classification
Help
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.
(11)
Help
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.
Uncertain significance
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000249.4(MLH1):c.1682A>G (p.Tyr561Cys)
Variation ID: 483536 Accession: VCV000483536.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37042282 (GRCh38) [ NCBI UCSC ] 3: 37083773 (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 Jan 1, 2018 Jun 17, 2024 Feb 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000249.4:c.1682A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Tyr561Cys missense NM_001167617.3:c.1388A>G NP_001161089.1:p.Tyr463Cys missense NM_001167618.3:c.959A>G NP_001161090.1:p.Tyr320Cys missense NM_001167619.3:c.959A>G NP_001161091.1:p.Tyr320Cys missense NM_001258271.2:c.1682A>G NP_001245200.1:p.Tyr561Cys missense NM_001258273.2:c.959A>G NP_001245202.1:p.Tyr320Cys missense NM_001258274.3:c.959A>G NP_001245203.1:p.Tyr320Cys missense NM_001354615.2:c.959A>G NP_001341544.1:p.Tyr320Cys missense NM_001354616.2:c.959A>G NP_001341545.1:p.Tyr320Cys missense NM_001354617.2:c.959A>G NP_001341546.1:p.Tyr320Cys missense NM_001354618.2:c.959A>G NP_001341547.1:p.Tyr320Cys missense NM_001354619.2:c.959A>G NP_001341548.1:p.Tyr320Cys missense NM_001354620.2:c.1388A>G NP_001341549.1:p.Tyr463Cys missense NM_001354621.2:c.659A>G NP_001341550.1:p.Tyr220Cys missense NM_001354622.2:c.659A>G NP_001341551.1:p.Tyr220Cys missense NM_001354623.2:c.659A>G NP_001341552.1:p.Tyr220Cys missense NM_001354624.2:c.608A>G NP_001341553.1:p.Tyr203Cys missense NM_001354625.2:c.608A>G NP_001341554.1:p.Tyr203Cys missense NM_001354626.2:c.608A>G NP_001341555.1:p.Tyr203Cys missense NM_001354627.2:c.608A>G NP_001341556.1:p.Tyr203Cys missense NM_001354628.2:c.1682A>G NP_001341557.1:p.Tyr561Cys missense NM_001354629.2:c.1583A>G NP_001341558.1:p.Tyr528Cys missense NM_001354630.2:c.1682A>G NP_001341559.1:p.Tyr561Cys missense NC_000003.12:g.37042282A>G NC_000003.11:g.37083773A>G NG_007109.2:g.53933A>G LRG_216:g.53933A>G LRG_216t1:c.1682A>G LRG_216p1:p.Tyr561Cys - Protein change
- Y561C, Y203C, Y220C, Y528C, Y320C, Y463C
- Other names
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p.Tyr561Cys
- Canonical SPDI
- NC_000003.12:37042281:A: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.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|||
| MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5691 | 5752 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000568554.8 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 22, 2024 | RCV000662503.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000796646.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002248787.1 | |
| Uncertain significance (3) |
criteria provided, single submitter
|
Mar 21, 2022 | RCV001701093.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 2, 2023 | RCV004001022.2 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Mar 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785026.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
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Uncertain significance
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518247.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
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Uncertain significance
(Mar 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020264.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
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Uncertain significance
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226067.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000936167.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the MLH1 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the MLH1 protein (p.Tyr561Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 10612827, 21520333). ClinVar contains an entry for this variant (Variation ID: 483536). 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%. 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
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909037.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
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Uncertain Significance
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004843193.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
|
|
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Uncertain significance
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000669524.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.Y561C variant (also known as c.1682A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide … (more)
The p.Y561C variant (also known as c.1682A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide position 1682. The tyrosine at codon 561 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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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Uncertain significance
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005057974.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919305.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001954484.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Comment:
Comment:
PP3
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the MLH1 protein (p.Tyr561Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 10612827, 21520333). ClinVar contains an entry for this variant (Variation ID: 483536). 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%. 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.
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.Y561C variant (also known as c.1682A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide position 1682. The tyrosine at codon 561 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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.
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:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
PP3
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the MLH1 protein (p.Tyr561Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 10612827, 21520333). ClinVar contains an entry for this variant (Variation ID: 483536). 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%. 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.
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.Y561C variant (also known as c.1682A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide position 1682. The tyrosine at codon 561 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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.
Citations for germline classification of this variant
HelpText-mined citations for rs1289807424 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.