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NM_000249.4(MLH1):c.925C>T (p.Pro309Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Sep 25, 2021)
Last evaluated:
Dec 24, 2020
Accession:
VCV000090444.9
Variation ID:
90444
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.925C>T (p.Pro309Ser)

Allele ID
95918
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37020350 (GRCh38) GRCh38 UCSC
3: 37061841 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P40692:p.Pro309Ser
NC_000003.11:g.37061841C>T
NM_000249.3:c.925C>T NP_000240.1:p.Pro309Ser missense
... more HGVS
Protein change
P309S, P276S, P211S, P68S
Other names
-
Canonical SPDI
NC_000003.12:37020349:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Links
ClinGen: CA013121
UniProtKB: P40692#VAR_038025
dbSNP: rs267607808
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Dec 24, 2020 RCV000486267.2
Uncertain significance 1 criteria provided, single submitter Oct 1, 2020 RCV000684787.3
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Apr 2, 2019 RCV000574268.5
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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
(Oct 01, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000259481.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
This sequence change replaces proline with serine at codon 309 of the MLH1 protein (p.Pro309Ser). The proline residue is highly conserved and there is a … (more)
Uncertain significance
(Apr 02, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000689930.3
Submitted: (May 19, 2020)
Evidence details
Likely benign
(Jan 30, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000662018.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (1)
Comment:
Subpopulation frequency in support of benign classification
Uncertain significance
(Dec 24, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000567201.4
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has 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
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
Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Barnetson RA Human mutation 2008 PMID: 18033691

Text-mined citations for rs267607808...

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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 Oct 30, 2021