NM_000249.4(MLH1):c.199G>C (p.Gly67Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 8, 2022
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:: RCV000700612.4

Allele description [Variation Report for NM_000249.4(MLH1):c.199G>C (p.Gly67Arg)]

NM_000249.4(MLH1):c.199G>C (p.Gly67Arg)

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.199G>C (p.Gly67Arg)

HGVS:

NC_000003.12:g.36996701G>C
NG_007109.2:g.8352G>C
NG_008418.1:g.1604C>G
NM_000249.4:c.199G>CMANE SELECT
NM_001167617.3:c.-91G>C
NM_001167618.3:c.-525G>C
NM_001167619.3:c.-433G>C
NM_001258271.2:c.199G>C
NM_001258273.2:c.-517+3038G>C
NM_001258274.3:c.-670G>C
NM_001354615.2:c.-428G>C
NM_001354616.2:c.-433G>C
NM_001354617.2:c.-525G>C
NM_001354618.2:c.-525G>C
NM_001354619.2:c.-525G>C
NM_001354620.2:c.-91G>C
NM_001354621.2:c.-618G>C
NM_001354622.2:c.-731G>C
NM_001354623.2:c.-723+2811G>C
NM_001354624.2:c.-628G>C
NM_001354625.2:c.-531G>C
NM_001354626.2:c.-628G>C
NM_001354627.2:c.-628G>C
NM_001354628.2:c.199G>C
NM_001354629.2:c.199G>C
NM_001354630.2:c.199G>C
NP_000240.1:p.Gly67Arg
NP_000240.1:p.Gly67Arg
NP_001245200.1:p.Gly67Arg
NP_001341557.1:p.Gly67Arg
NP_001341558.1:p.Gly67Arg
NP_001341559.1:p.Gly67Arg
LRG_216t1:c.199G>C
LRG_216:g.8352G>C
LRG_216p1:p.Gly67Arg
NC_000003.11:g.37038192G>C
NM_000249.3:c.199G>C

Protein change:

G67R

Links:

dbSNP: rs63750206

NCBI 1000 Genomes Browser:

rs63750206

Molecular consequence:

NM_001167617.3:c.-91G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-433G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-670G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-428G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-433G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-91G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-618G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-731G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-628G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-531G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-628G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-628G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3038G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2811G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000829374	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 8, 2022)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 9697702, 11555625, 12810663, 18094436, 18337503, 8521398, 12419761, 15563510, 15613555, 16083711, 17312306, 18383312, 21239990, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829374

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 8, 2022)

germline

clinical testing

PubMed (14)
[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

Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae.

Shimodaira H, Filosi N, Shibata H, Suzuki T, Radice P, Kanamaru R, Friend SH, Kolodner RD, Ishioka C.

Nat Genet. 1998 Aug;19(4):384-9. Erratum in: Nat Genet 1999 Feb;21(2):241.

PubMed [citation]

PMID:: 9697702

Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.

Ellison AR, Lofing J, Bitter GA.

Hum Mol Genet. 2001 Sep 1;10(18):1889-900.

PubMed [citation]

PMID:: 11555625

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829374.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly67 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8521398, 12419761, 15563510, 15613555, 17312306, 18383312, 21239990). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11555625, 12810663, 16083711, 18094436, 18337503). 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. ClinVar contains an entry for this variant (Variation ID: 495763). This missense change has been observed in individual(s) with colorectal cancer (PMID: 8521398, 12419761, 15563510, 15613555, 16083711, 17312306, 18383312, 21239990). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 67 of the MLH1 protein (p.Gly67Arg).

#	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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