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NM_000249.4(MLH1):c.292G>C (p.Gly98Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 5, 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:
RCV000693726.4

Allele description

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)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000821607Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Oct 5, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Multiplex SNaPshot genotyping for detecting loss of heterozygosity in the mismatch-repair genes MLH1 and MSH2 in microsatellite-unstable tumors.

Bujalkova M, Zavodna K, Krivulcik T, Ilencikova D, Wolf B, Kovac M, Karner-Hanusch J, Heinimann K, Marra G, Jiricny J, Bartosova Z.

Clin Chem. 2008 Nov;54(11):1844-54. doi: 10.1373/clinchem.2008.108902. Epub 2008 Sep 4.

PubMed [citation]
PMID:
18772310

Familial colorectal cancer: eleven years of data from a registry program in Switzerland.

Kovac M, Laczko E, Haider R, Jiricny J, Mueller H, Heinimann K, Marra G.

Fam Cancer. 2011 Sep;10(3):605-16. doi: 10.1007/s10689-011-9458-6.

PubMed [citation]
PMID:
21671081
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000821607.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the MLH1 protein (p.Gly98Arg). This variant is present in population databases (rs267607725, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 18772310, 21671081). ClinVar contains an entry for this variant (Variation ID: 90129). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This variant disrupts the p.Gly98 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18561205, 22290698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 19, 2024