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

This record was updated by the submitter. Please see the current version.

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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gi|11071735|emb|CAC14668.1|

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potassium channel AKT2 [Sorghum bicolor]
gi|242090625|ref|XP_002441145.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000821607	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18772310, 21671081, 18561205, 22290698, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000821607

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 5, 2023)

germline

clinical testing

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

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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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: May 19, 2024

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