Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 229812). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25503501, 34347074). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 725 of the MLH1 protein (p.Arg725Gly).
ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2173C>G (p.Arg725Gly)
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.
(6)
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
6
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.2173C>G (p.Arg725Gly)
Variation ID: 229812 Accession: VCV000229812.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 37050555 (GRCh38) [ NCBI UCSC ] 3: 37092046 (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 Apr 17, 2017 Jun 17, 2024 Feb 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000249.4:c.2173C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Arg725Gly missense NM_001167617.3:c.1879C>G NP_001161089.1:p.Arg627Gly missense NM_001167618.3:c.1450C>G NP_001161090.1:p.Arg484Gly missense NM_001167619.3:c.1450C>G NP_001161091.1:p.Arg484Gly missense NM_001258271.2:c.1966C>G NP_001245200.1:p.Arg656Gly missense NM_001258273.2:c.1450C>G NP_001245202.1:p.Arg484Gly missense NM_001258274.3:c.1450C>G NP_001245203.1:p.Arg484Gly missense NM_001354615.2:c.1450C>G NP_001341544.1:p.Arg484Gly missense NM_001354616.2:c.1450C>G NP_001341545.1:p.Arg484Gly missense NM_001354617.2:c.1450C>G NP_001341546.1:p.Arg484Gly missense NM_001354618.2:c.1450C>G NP_001341547.1:p.Arg484Gly missense NM_001354619.2:c.1450C>G NP_001341548.1:p.Arg484Gly missense NM_001354620.2:c.1879C>G NP_001341549.1:p.Arg627Gly missense NM_001354621.2:c.1150C>G NP_001341550.1:p.Arg384Gly missense NM_001354622.2:c.1150C>G NP_001341551.1:p.Arg384Gly missense NM_001354623.2:c.1150C>G NP_001341552.1:p.Arg384Gly missense NM_001354624.2:c.1099C>G NP_001341553.1:p.Arg367Gly missense NM_001354625.2:c.1099C>G NP_001341554.1:p.Arg367Gly missense NM_001354626.2:c.1099C>G NP_001341555.1:p.Arg367Gly missense NM_001354627.2:c.1099C>G NP_001341556.1:p.Arg367Gly missense NM_001354628.2:c.2080C>G NP_001341557.1:p.Arg694Gly missense NM_001354629.2:c.2074C>G NP_001341558.1:p.Arg692Gly missense NM_001354630.2:c.2008C>G NP_001341559.1:p.Arg670Gly missense NC_000003.12:g.37050555C>G NC_000003.11:g.37092046C>G NG_007109.2:g.62206C>G LRG_216:g.62206C>G LRG_216t1:c.2173C>G LRG_216p1:p.Arg725Gly - Protein change
- R725G, R627G, R694G, R484G, R367G, R656G, R670G, R384G, R692G
- Other names
- -
- Canonical SPDI
- NC_000003.12:37050554:C:G
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 (1) |
criteria provided, single submitter
|
Feb 12, 2021 | RCV000217046.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 1, 2023 | RCV000461789.5 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000663259.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 18, 2023 | RCV003997772.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543651.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 229812). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25503501, 34347074). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 725 of the MLH1 protein (p.Arg725Gly). (less)
|
|
|
Uncertain significance
(Feb 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273152.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R725G variant (also known as c.2173C>G), located in coding exon 19 of the MLH1 gene, results from a C to G substitution at nucleotide … (more)
The p.R725G variant (also known as c.2173C>G), located in coding exon 19 of the MLH1 gene, results from a C to G substitution at nucleotide position 2173. The arginine at codon 725 is replaced by glycine, an amino acid with dissimilar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8). 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)
|
|
|
Uncertain significance
(May 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786487.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
|
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: SCV004020263.1
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.
|
|
|
Uncertain Significance
(Dec 18, 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: SCV004843292.1
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 arginine with glycine at codon 725 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glycine at codon 725 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 been reported in at least one individual with early onset breast cancer (PMID: 25503501) as well as an individual affected with colorectal cancer (PMID: 34347074). This variant has been identified in 2/251148 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: 3
|
|
|
Uncertain significance
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005057988.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
The p.R725G variant (also known as c.2173C>G), located in coding exon 19 of the MLH1 gene, results from a C to G substitution at nucleotide position 2173. The arginine at codon 725 is replaced by glycine, an amino acid with dissimilar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8). 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.
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:
This missense variant replaces arginine with glycine at codon 725 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 been reported in at least one individual with early onset breast cancer (PMID: 25503501) as well as an individual affected with colorectal cancer (PMID: 34347074). This variant has been identified in 2/251148 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.
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:
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 229812). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25503501, 34347074). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 725 of the MLH1 protein (p.Arg725Gly).
Comment:
The p.R725G variant (also known as c.2173C>G), located in coding exon 19 of the MLH1 gene, results from a C to G substitution at nucleotide position 2173. The arginine at codon 725 is replaced by glycine, an amino acid with dissimilar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8). 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.
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:
This missense variant replaces arginine with glycine at codon 725 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 been reported in at least one individual with early onset breast cancer (PMID: 25503501) as well as an individual affected with colorectal cancer (PMID: 34347074). This variant has been identified in 2/251148 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline Alterations in Patients With IBD-associated Colorectal Cancer. | Biscaglia G | Inflammatory bowel diseases | 2022 | PMID: 34347074 |
| Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
Text-mined citations for rs138584384 ...
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.