NM_000249.4(MLH1):c.193G>C (p.Gly65Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 9, 2021
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:: RCV002047856.4

Allele description [Variation Report for NM_000249.4(MLH1):c.193G>C (p.Gly65Arg)]

NM_000249.4(MLH1):c.193G>C (p.Gly65Arg)

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.193G>C (p.Gly65Arg)

HGVS:

NC_000003.12:g.36996695G>C
NG_007109.2:g.8346G>C
NG_008418.1:g.1610C>G
NM_000249.4:c.193G>CMANE SELECT
NM_001167617.3:c.-97G>C
NM_001167618.3:c.-531G>C
NM_001167619.3:c.-439G>C
NM_001258271.2:c.193G>C
NM_001258273.2:c.-517+3032G>C
NM_001258274.3:c.-676G>C
NM_001354615.2:c.-434G>C
NM_001354616.2:c.-439G>C
NM_001354617.2:c.-531G>C
NM_001354618.2:c.-531G>C
NM_001354619.2:c.-531G>C
NM_001354620.2:c.-97G>C
NM_001354621.2:c.-624G>C
NM_001354622.2:c.-737G>C
NM_001354623.2:c.-723+2805G>C
NM_001354624.2:c.-634G>C
NM_001354625.2:c.-537G>C
NM_001354626.2:c.-634G>C
NM_001354627.2:c.-634G>C
NM_001354628.2:c.193G>C
NM_001354629.2:c.193G>C
NM_001354630.2:c.193G>C
NP_000240.1:p.Gly65Arg
NP_001245200.1:p.Gly65Arg
NP_001341557.1:p.Gly65Arg
NP_001341558.1:p.Gly65Arg
NP_001341559.1:p.Gly65Arg
LRG_216:g.8346G>C
NC_000003.11:g.37038186G>C

Protein change:

G65R

Links:

dbSNP: rs2081173076

NCBI 1000 Genomes Browser:

rs2081173076

Molecular consequence:

NM_001167617.3:c.-97G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-531G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-439G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-676G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-434G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-439G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-531G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-531G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-531G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-97G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-624G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-737G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-634G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-537G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-634G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-634G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3032G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2805G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.193G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.193G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.193G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.193G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.193G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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BDBG_00014 [Blastomyces gilchristii SLH14081]
BDBG_00014 [Blastomyces gilchristii SLH14081]
Gene ID:8507609

Gene
BDBG_00014 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002296629	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 9, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15475387, 18094436, 23403630, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002296629

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 9, 2021)

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

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Analysis of hMLH1 missense mutations in East Asian patients with suspected hereditary nonpolyposis colorectal cancer.

Fan Y, Wang W, Zhu M, Zhou J, Peng J, Xu L, Hua Z, Gao X, Wang Y.

Clin Cancer Res. 2007 Dec 15;13(24):7515-21.

PubMed [citation]

PMID:: 18094436

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002296629.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the p.Gly65 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15475387, 18094436, 23403630, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 has not been reported in the literature in individuals affected with MLH1-related conditions. This sequence change replaces glycine with arginine at codon 65 of the MLH1 protein (p.Gly65Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.

#	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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