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NM_000249.4(MLH1):c.2262G>T (p.Glu754Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 25, 2016
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000565798.3

Allele description [Variation Report for NM_000249.4(MLH1):c.2262G>T (p.Glu754Asp)]

NM_000249.4(MLH1):c.2262G>T (p.Glu754Asp)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.2262G>T (p.Glu754Asp)
HGVS:
  • NC_000003.12:g.37050644G>T
  • NG_007109.2:g.62295G>T
  • NG_053016.1:g.131174C>A
  • NM_000249.4:c.2262G>TMANE SELECT
  • NM_001167617.3:c.1968G>T
  • NM_001167618.3:c.1539G>T
  • NM_001167619.3:c.1539G>T
  • NM_001258271.2:c.2055G>T
  • NM_001258273.2:c.1539G>T
  • NM_001258274.3:c.1539G>T
  • NM_001354615.2:c.1539G>T
  • NM_001354616.2:c.1539G>T
  • NM_001354617.2:c.1539G>T
  • NM_001354618.2:c.1539G>T
  • NM_001354619.2:c.1539G>T
  • NM_001354620.2:c.1968G>T
  • NM_001354621.2:c.1239G>T
  • NM_001354622.2:c.1239G>T
  • NM_001354623.2:c.1239G>T
  • NM_001354624.2:c.1188G>T
  • NM_001354625.2:c.1188G>T
  • NM_001354626.2:c.1188G>T
  • NM_001354627.2:c.1188G>T
  • NM_001354628.2:c.2169G>T
  • NM_001354629.2:c.2163G>T
  • NM_001354630.2:c.2097G>T
  • NP_000240.1:p.Glu754Asp
  • NP_000240.1:p.Glu754Asp
  • NP_001161089.1:p.Glu656Asp
  • NP_001161090.1:p.Glu513Asp
  • NP_001161091.1:p.Glu513Asp
  • NP_001245200.1:p.Glu685Asp
  • NP_001245202.1:p.Glu513Asp
  • NP_001245203.1:p.Glu513Asp
  • NP_001341544.1:p.Glu513Asp
  • NP_001341545.1:p.Glu513Asp
  • NP_001341546.1:p.Glu513Asp
  • NP_001341547.1:p.Glu513Asp
  • NP_001341548.1:p.Glu513Asp
  • NP_001341549.1:p.Glu656Asp
  • NP_001341550.1:p.Glu413Asp
  • NP_001341551.1:p.Glu413Asp
  • NP_001341552.1:p.Glu413Asp
  • NP_001341553.1:p.Glu396Asp
  • NP_001341554.1:p.Glu396Asp
  • NP_001341555.1:p.Glu396Asp
  • NP_001341556.1:p.Glu396Asp
  • NP_001341557.1:p.Glu723Asp
  • NP_001341558.1:p.Glu721Asp
  • NP_001341559.1:p.Glu699Asp
  • LRG_216t1:c.2262G>T
  • LRG_216:g.62295G>T
  • LRG_216p1:p.Glu754Asp
  • NC_000003.11:g.37092135G>T
  • NM_000249.3:c.2262G>T
Protein change:
E396D
Links:
dbSNP: rs1553666101
NCBI 1000 Genomes Browser:
rs1553666101
Molecular consequence:
  • NM_000249.4:c.2262G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1968G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.2055G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1539G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1968G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1239G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1239G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1239G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.1188G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.1188G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.1188G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.1188G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.2169G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.2163G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.2097G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000673839Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Aug 25, 2016) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV000673839.5

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

Description

The p.E754D variant (also known as c.2262G>T), located in coding exon 19 of the MLH1 gene, results from a G to T substitution at nucleotide position 2262. The glutamic acid at codon 754 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024