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NM_000249.4(MLH1):c.292G>C (p.Gly98Arg) AND not provided

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 28, 2015
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:
RCV000216356.1

Allele description [Variation Report for NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)]

NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)

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.292G>C (p.Gly98Arg)
HGVS:
  • NC_000003.12:g.37001039G>C
  • NG_007109.2:g.12690G>C
  • NM_000249.4:c.292G>CMANE SELECT
  • NM_001167617.3:c.3G>C
  • NM_001167618.3:c.-432G>C
  • NM_001167619.3:c.-340G>C
  • NM_001258271.2:c.292G>C
  • NM_001258273.2:c.-432G>C
  • NM_001258274.3:c.-432G>C
  • NM_001354615.2:c.-335G>C
  • NM_001354616.2:c.-340G>C
  • NM_001354617.2:c.-432G>C
  • NM_001354618.2:c.-432G>C
  • NM_001354619.2:c.-432G>C
  • NM_001354620.2:c.3G>C
  • NM_001354621.2:c.-525G>C
  • NM_001354622.2:c.-638G>C
  • NM_001354623.2:c.-638G>C
  • NM_001354624.2:c.-535G>C
  • NM_001354625.2:c.-438G>C
  • NM_001354626.2:c.-535G>C
  • NM_001354627.2:c.-535G>C
  • NM_001354628.2:c.292G>C
  • NM_001354629.2:c.208-3362G>C
  • NM_001354630.2:c.292G>C
  • NP_000240.1:p.Gly98Arg
  • NP_000240.1:p.Gly98Arg
  • NP_001161089.1:p.Met1Ile
  • NP_001245200.1:p.Gly98Arg
  • NP_001341549.1:p.Met1Ile
  • NP_001341557.1:p.Gly98Arg
  • NP_001341559.1:p.Gly98Arg
  • LRG_216t1:c.292G>C
  • LRG_216:g.12690G>C
  • LRG_216p1:p.Gly98Arg
  • NC_000003.11:g.37042530G>C
  • NM_000249.3:c.292G>C
  • NM_001167618.1:c.-432G>C
Protein change:
G98R
Links:
dbSNP: rs267607725
NCBI 1000 Genomes Browser:
rs267607725
Molecular consequence:
  • NM_001167618.3:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-340G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-340G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-638G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-638G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-438G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167617.3:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354620.2:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354629.2:c.208-3362G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.292G>C - 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
SCV000279070GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Uncertain significance
(Sep 28, 2015) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000279070.10

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

Description

This variant is denoted MLH1 c.292G>C at the cDNA level, p.Gly98Arg (G98R) at the protein level, and results in the change of a Glycine to an Arginine (GGC>CGC). This variant has been reported in one individual with either colorectal or urothelial cancer and in an individual meeting Amsterdam II criteria whose tumor showed microsatellite instability (MSI-H) but intact expression of the mismatch repair proteins by immunohistochemistry (IHC) (Bujalkova 2008, Kovac 2011). MLH1 Gly98Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly98Arg occurs at a position that is conserved across species and is located in the ATPase domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as one of uncertain significance based on insufficient evidence (Thompson 2014). Based on currently available evidence, we consider MLH1 Gly98Arg to be a variant of uncertain significance.

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

Last Updated: Sep 29, 2024