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NM_000249.4(MLH1):c.1253A>G (p.Asp418Gly) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Sep 13, 2023
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:
RCV000482366.5

Allele description [Variation Report for NM_000249.4(MLH1):c.1253A>G (p.Asp418Gly)]

NM_000249.4(MLH1):c.1253A>G (p.Asp418Gly)

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.1253A>G (p.Asp418Gly)
HGVS:
  • NC_000003.12:g.37025851A>G
  • NG_007109.2:g.37502A>G
  • NM_000249.4:c.1253A>GMANE SELECT
  • NM_001167617.3:c.959A>G
  • NM_001167618.3:c.530A>G
  • NM_001167619.3:c.530A>G
  • NM_001258271.2:c.1253A>G
  • NM_001258273.2:c.530A>G
  • NM_001258274.3:c.530A>G
  • NM_001354615.2:c.530A>G
  • NM_001354616.2:c.530A>G
  • NM_001354617.2:c.530A>G
  • NM_001354618.2:c.530A>G
  • NM_001354619.2:c.530A>G
  • NM_001354620.2:c.959A>G
  • NM_001354621.2:c.230A>G
  • NM_001354622.2:c.230A>G
  • NM_001354623.2:c.230A>G
  • NM_001354624.2:c.179A>G
  • NM_001354625.2:c.179A>G
  • NM_001354626.2:c.179A>G
  • NM_001354627.2:c.179A>G
  • NM_001354628.2:c.1253A>G
  • NM_001354629.2:c.1154A>G
  • NM_001354630.2:c.1253A>G
  • NP_000240.1:p.Asp418Gly
  • NP_000240.1:p.Asp418Gly
  • NP_001161089.1:p.Asp320Gly
  • NP_001161090.1:p.Asp177Gly
  • NP_001161091.1:p.Asp177Gly
  • NP_001245200.1:p.Asp418Gly
  • NP_001245202.1:p.Asp177Gly
  • NP_001245203.1:p.Asp177Gly
  • NP_001341544.1:p.Asp177Gly
  • NP_001341545.1:p.Asp177Gly
  • NP_001341546.1:p.Asp177Gly
  • NP_001341547.1:p.Asp177Gly
  • NP_001341548.1:p.Asp177Gly
  • NP_001341549.1:p.Asp320Gly
  • NP_001341550.1:p.Asp77Gly
  • NP_001341551.1:p.Asp77Gly
  • NP_001341552.1:p.Asp77Gly
  • NP_001341553.1:p.Asp60Gly
  • NP_001341554.1:p.Asp60Gly
  • NP_001341555.1:p.Asp60Gly
  • NP_001341556.1:p.Asp60Gly
  • NP_001341557.1:p.Asp418Gly
  • NP_001341558.1:p.Asp385Gly
  • NP_001341559.1:p.Asp418Gly
  • LRG_216t1:c.1253A>G
  • LRG_216:g.37502A>G
  • LRG_216p1:p.Asp418Gly
  • NC_000003.11:g.37067342A>G
  • NM_000249.3:c.1253A>G
Protein change:
D177G
Links:
dbSNP: rs754898711
NCBI 1000 Genomes Browser:
rs754898711
Molecular consequence:
  • NM_000249.4:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.530A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.179A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.179A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.179A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.179A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1154A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000573497GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(Sep 13, 2023) 		germlineclinical testing

Citation Link,

SCV001552793Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Help

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, SCV000573497.5

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 22753075, 27121310, 28135145, 32885271)

#SampleMethodObservation
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), SCV001552793.1

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

Description

The MLH1 p.Asp418Gly variant was not identified in the literature nor was it identified in the UMD-LSDB databases. The variant was identified in dbSNP (rs754898711) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 1 of 251,348 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 113,640 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Asp418 residue is not conserved in mammals and 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 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5’ splice donor site. However, this information is not predictive enough to assume pathogenicity. 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.

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

Last Updated: Sep 29, 2024