NM_000249.4(MLH1):c.292G>C (p.Gly98Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 2, 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:: RCV001017525.4

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)

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001178615	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 2, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10199405, 18772310, 21671081, 26249686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001178615

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 2, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair.

Ban C, Junop M, Yang W.

Cell. 1999 Apr 2;97(1):85-97.

PubMed [citation]

PMID:: 10199405

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

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001178615.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.G98R variant (also known as c.292G>C), located in coding exon 3 of the MLH1 gene, results from a G to C substitution at nucleotide position 292. The glycine at codon 98 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a patient with non-polyposis colon cancer and a family history that met Amsterdam II criteria. Also, the tumor of this proband displayed high microsatellite instability (MSI-H), but demonstrated normal expression of all four mismatch repair proteins (Kovac MI et al. Fam. Cancer. 2011;10(3):605-16). In another report, this alteration was identified in an individual whose tumor, either colorectal or urothelial, was MSI-H (Bujalkova M et al. Clin. Chem. 2008 Nov;54:1844-54). Based on an internal structural analysis, this alteration blocks the ATP binding site (Ban C et al. Cell. 1999 Apr;97:85-97; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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