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NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(6)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Sep 24, 2021)
Last evaluated:
Oct 12, 2020
Accession:
VCV000216337.10
Variation ID:
216337
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)

Allele ID
212297
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 36993627 (GRCh38) GRCh38 UCSC
3: 37035118 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000003.11:g.37035118G>A
NM_000249.3:c.80G>A NP_000240.1:p.Arg27Gln missense
LRG_216:g.5278G>A
... more HGVS
Protein change
R27Q
Other names
-
Canonical SPDI
NC_000003.12:36993626:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
Links
ClinGen: CA038485
dbSNP: rs138705565
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 3 criteria provided, multiple submitters, no conflicts Aug 25, 2020 RCV000587717.3
Uncertain significance 1 criteria provided, single submitter Oct 12, 2020 RCV000197307.8
Uncertain significance 1 criteria provided, single submitter Nov 20, 2017 RCV000662868.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Apr 19, 2019 RCV000573727.5
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MLH1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3503 3539

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Aug 09, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696182.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (1)
Comment:
Variant summary: The MLH1 c.80G>A (p.Arg27Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the histidine kinase-like ATPase, C-terminal … (more)
Uncertain significance
(Nov 20, 2017)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome II
Allele origin: unknown
Counsyl
Accession: SCV000785757.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Mar 21, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889404.2
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Feb 20, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000689923.3
Submitted: (May 19, 2020)
Evidence details
Likely benign
(Apr 19, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000662012.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (1)
Comment:
Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Uncertain significance
(Oct 12, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000254372.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces arginine with glutamine at codon 27 of the MLH1 protein (p.Arg27Gln). The arginine residue is highly conserved and there is a … (more)
Uncertain significance
(Aug 25, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000279261.7
Submitted: (Sep 24, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting. Clarke EV Familial cancer 2019 PMID: 30729418
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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 rs138705565...

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These 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 Nov 27, 2021