NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Mar 14, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu)]

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

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.1103C>T (p.Ser368Leu)
  • NC_000003.12:g.37025701C>T
  • NG_007109.2:g.37352C>T
  • NM_000249.3:c.1103C>T
  • NM_000249.4:c.1103C>TMANE SELECT
  • NM_001167617.3:c.809C>T
  • NM_001167618.3:c.380C>T
  • NM_001167619.3:c.380C>T
  • NM_001258271.2:c.1103C>T
  • NM_001258273.2:c.380C>T
  • NM_001258274.3:c.380C>T
  • NM_001354615.2:c.380C>T
  • NM_001354616.2:c.380C>T
  • NM_001354617.2:c.380C>T
  • NM_001354618.2:c.380C>T
  • NM_001354619.2:c.380C>T
  • NM_001354620.2:c.809C>T
  • NM_001354621.2:c.80C>T
  • NM_001354622.2:c.80C>T
  • NM_001354623.2:c.80C>T
  • NM_001354624.2:c.29C>T
  • NM_001354625.2:c.29C>T
  • NM_001354626.2:c.29C>T
  • NM_001354627.2:c.29C>T
  • NM_001354628.2:c.1103C>T
  • NM_001354629.2:c.1004C>T
  • NM_001354630.2:c.1103C>T
  • NP_000240.1:p.Ser368Leu
  • NP_000240.1:p.Ser368Leu
  • NP_001161089.1:p.Ser270Leu
  • NP_001161090.1:p.Ser127Leu
  • NP_001161091.1:p.Ser127Leu
  • NP_001245200.1:p.Ser368Leu
  • NP_001245202.1:p.Ser127Leu
  • NP_001245203.1:p.Ser127Leu
  • NP_001341544.1:p.Ser127Leu
  • NP_001341545.1:p.Ser127Leu
  • NP_001341546.1:p.Ser127Leu
  • NP_001341547.1:p.Ser127Leu
  • NP_001341548.1:p.Ser127Leu
  • NP_001341549.1:p.Ser270Leu
  • NP_001341550.1:p.Ser27Leu
  • NP_001341551.1:p.Ser27Leu
  • NP_001341552.1:p.Ser27Leu
  • NP_001341553.1:p.Ser10Leu
  • NP_001341554.1:p.Ser10Leu
  • NP_001341555.1:p.Ser10Leu
  • NP_001341556.1:p.Ser10Leu
  • NP_001341557.1:p.Ser368Leu
  • NP_001341558.1:p.Ser335Leu
  • NP_001341559.1:p.Ser368Leu
  • LRG_216t1:c.1103C>T
  • LRG_216:g.37352C>T
  • LRG_216p1:p.Ser368Leu
  • NC_000003.11:g.37067192C>T
  • p.S368L
Protein change:
dbSNP: rs201673334
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.3:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000249.4:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.809C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.380C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.809C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.80C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.80C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.80C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.29C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.29C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.29C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.29C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1004C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000571090GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 14, 2018)
germlineclinical testing

Citation Link,

SCV001552494Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000571090.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


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 a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. MLH1 Ser368Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Ser368Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552494.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


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: rs201673334) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, and GeneDx; and as likely benign by Color). The variant was identified in control databases in 6 of 276576 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 6 of 18846 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, European (Finnish), or South Asian populations. The variant was identified in our laboratory with a co-occurring, pathogenic POLE variant (c.6747+1G>A, r.spl?), increasing the likelihood that the p.Ser368Leu variant does not have clinical significance. The p.Ser368 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 6, 2021

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