NM_000249.4(MLH1):c.1136A>C (p.Tyr379Ser) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jun 11, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.1136A>C (p.Tyr379Ser)]

NM_000249.4(MLH1):c.1136A>C (p.Tyr379Ser)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.1136A>C (p.Tyr379Ser)
  • NC_000003.12:g.37025734A>C
  • NG_007109.2:g.37385A>C
  • NM_000249.4:c.1136A>CMANE SELECT
  • NM_001167617.3:c.842A>C
  • NM_001167618.3:c.413A>C
  • NM_001167619.3:c.413A>C
  • NM_001258271.2:c.1136A>C
  • NM_001258273.2:c.413A>C
  • NM_001258274.3:c.413A>C
  • NM_001354615.2:c.413A>C
  • NM_001354616.2:c.413A>C
  • NM_001354617.2:c.413A>C
  • NM_001354618.2:c.413A>C
  • NM_001354619.2:c.413A>C
  • NM_001354620.2:c.842A>C
  • NM_001354621.2:c.113A>C
  • NM_001354622.2:c.113A>C
  • NM_001354623.2:c.113A>C
  • NM_001354624.2:c.62A>C
  • NM_001354625.2:c.62A>C
  • NM_001354626.2:c.62A>C
  • NM_001354627.2:c.62A>C
  • NM_001354628.2:c.1136A>C
  • NM_001354629.2:c.1037A>C
  • NM_001354630.2:c.1136A>C
  • NP_000240.1:p.Tyr379Ser
  • NP_000240.1:p.Tyr379Ser
  • NP_001161089.1:p.Tyr281Ser
  • NP_001161090.1:p.Tyr138Ser
  • NP_001161091.1:p.Tyr138Ser
  • NP_001245200.1:p.Tyr379Ser
  • NP_001245202.1:p.Tyr138Ser
  • NP_001245203.1:p.Tyr138Ser
  • NP_001341544.1:p.Tyr138Ser
  • NP_001341545.1:p.Tyr138Ser
  • NP_001341546.1:p.Tyr138Ser
  • NP_001341547.1:p.Tyr138Ser
  • NP_001341548.1:p.Tyr138Ser
  • NP_001341549.1:p.Tyr281Ser
  • NP_001341550.1:p.Tyr38Ser
  • NP_001341551.1:p.Tyr38Ser
  • NP_001341552.1:p.Tyr38Ser
  • NP_001341553.1:p.Tyr21Ser
  • NP_001341554.1:p.Tyr21Ser
  • NP_001341555.1:p.Tyr21Ser
  • NP_001341556.1:p.Tyr21Ser
  • NP_001341557.1:p.Tyr379Ser
  • NP_001341558.1:p.Tyr346Ser
  • NP_001341559.1:p.Tyr379Ser
  • LRG_216t1:c.1136A>C
  • LRG_216:g.37385A>C
  • LRG_216p1:p.Tyr379Ser
  • NC_000003.11:g.37067225A>C
  • NM_000249.3:c.1136A>C
  • p.Y379S
Protein change:
dbSNP: rs143009528
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.4:c.1136A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.842A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1136A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.413A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.842A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.113A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.113A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.113A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.62A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.62A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.62A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.62A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1136A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1037A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1136A>C - missense variant - [Sequence Ontology: SO:0001583]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000217748Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jun 11, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000904057Color Health, Inccriteria provided, single submitter
Likely benign
(Jan 13, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Identification of a mutL‑homolog 1 mutation via whole‑exome sequencing in a Chinese family with Gardner syndrome.

Lv Z, Wang C, Wu L, Guo B, Zhang D, Zhang Y, Huang S, Ou M.

Mol Med Rep. 2018 Jul;18(1):987-992. doi: 10.3892/mmr.2018.9063. Epub 2018 May 23.

PubMed [citation]

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000217748.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)


<p style="text-align:justify">The p.Y379S variant (also known as c.1136A>C), located in coding exon 12 of the MLH1 gene, results from an A to C substitution at nucleotide position 1136. The tyrosine at codon 379 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000904057.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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