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NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(5)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Nov 4, 2021)
Last evaluated:
Nov 3, 2021
Accession:
VCV000183738.10
Variation ID:
183738
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu)

Allele ID
182255
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37025701 (GRCh38) GRCh38 UCSC
3: 37067192 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000003.11:g.37067192C>T
NM_000249.3:c.1103C>T NP_000240.1:p.Ser368Leu missense
LRG_216:g.37352C>T
... more HGVS
Protein change
S368L, S10L, S270L, S335L, S127L, S27L
Other names
-
Canonical SPDI
NC_000003.12:37025700:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (T)

Allele frequency
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Links
ClinGen: CA004353
dbSNP: rs201673334
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, single submitter Mar 14, 2018 RCV000483837.2
Uncertain significance 1 criteria provided, single submitter Apr 12, 2020 RCV000476166.5
Uncertain significance 1 criteria provided, single submitter May 1, 2018 RCV000758575.1
Uncertain significance 1 criteria provided, single submitter Nov 3, 2021 RCV001762356.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Oct 10, 2018 RCV000162449.4
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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 10, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000212802.5
Submitted: (Nov 30, 2020)
Evidence details
Comment:
The p.S368L variant (also known as c.1103C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide … (more)
Uncertain significance
(May 01, 2018)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome
Allele origin: somatic
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887317.1
Submitted: (Dec 28, 2018)
Evidence details
Publications
PubMed (1)
Comment:
MLH1 NM_000249.3:c.1103C>T has a 14.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated … (more)
Uncertain significance
(Mar 14, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000571090.4
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This variant is denoted MLH1 c.1103C>T at the cDNA level, p.Ser368Leu (S368L) at the protein level, and results in the change of a Serine to … (more)
Likely benign
(Jun 02, 2017)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000911262.1
Submitted: (Nov 06, 2018)
Evidence details
Uncertain significance
(Apr 12, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000543561.6
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Comment:
This sequence change replaces serine with leucine at codon 368 of the MLH1 protein (p.Ser368Leu). The serine residue is moderately conserved and there is a … (more)
Uncertain significance
(Nov 03, 2021)
criteria provided, single submitter
Method: clinical testing
Muir-Torré syndrome
Allele origin: germline
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009381.1
Submitted: (Nov 04, 2021)
Evidence details
Uncertain significance
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: unknown
Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552494.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The MLH1 p.Ser368Leu variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: … (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
Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. Shirts BH American journal of human genetics 2018 PMID: 29887214
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

Text-mined citations for rs201673334...

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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