NM_000249.4(MLH1):c.142C>G (p.Gln48Glu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 21, 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:: RCV000805962.5

Allele description [Variation Report for NM_000249.4(MLH1):c.142C>G (p.Gln48Glu)]

NM_000249.4(MLH1):c.142C>G (p.Gln48Glu)

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.142C>G (p.Gln48Glu)

HGVS:

NC_000003.12:g.36996644C>G
NG_007109.2:g.8295C>G
NG_008418.1:g.1661G>C
NM_000249.4:c.142C>GMANE SELECT
NM_001167617.3:c.-148C>G
NM_001167618.3:c.-582C>G
NM_001167619.3:c.-490C>G
NM_001258271.2:c.142C>G
NM_001258273.2:c.-517+2981C>G
NM_001258274.3:c.-727C>G
NM_001354615.2:c.-485C>G
NM_001354616.2:c.-490C>G
NM_001354617.2:c.-582C>G
NM_001354618.2:c.-582C>G
NM_001354619.2:c.-582C>G
NM_001354620.2:c.-148C>G
NM_001354621.2:c.-675C>G
NM_001354622.2:c.-788C>G
NM_001354623.2:c.-723+2754C>G
NM_001354624.2:c.-685C>G
NM_001354625.2:c.-588C>G
NM_001354626.2:c.-685C>G
NM_001354627.2:c.-685C>G
NM_001354628.2:c.142C>G
NM_001354629.2:c.142C>G
NM_001354630.2:c.142C>G
NP_000240.1:p.Gln48Glu
NP_000240.1:p.Gln48Glu
NP_001245200.1:p.Gln48Glu
NP_001341557.1:p.Gln48Glu
NP_001341558.1:p.Gln48Glu
NP_001341559.1:p.Gln48Glu
LRG_216t1:c.142C>G
LRG_216:g.8295C>G
LRG_216p1:p.Gln48Glu
NC_000003.11:g.37038135C>G
NM_000249.3:c.142C>G

Protein change:

Q48E

Links:

dbSNP: rs587778913

NCBI 1000 Genomes Browser:

rs587778913

Molecular consequence:

NM_001167617.3:c.-148C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-582C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-490C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-727C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-485C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-490C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-582C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-582C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-582C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-148C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-675C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-788C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-685C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-588C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-685C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-685C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2981C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2754C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.142C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.142C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.142C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.142C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.142C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Mixture/Component Compounds for PubChem Compound (Select 16133090... (7)
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PubChem Compound
Streptomyces beijiangensis strain JCM 11882 genome sample
Streptomyces beijiangensis strain JCM 11882 genome sample

biosample
BioSample for Assembly (Select 22554301) (1)
BioSample
Taxonomy for Assembly (Select 22554301) (1)
Taxonomy
tRNA dihydrouridine synthase DusB [Thioalkalivibrio sp. AKL17]
tRNA dihydrouridine synthase DusB [Thioalkalivibrio sp. AKL17]
gi|517777288|ref|WP_018947496.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000945938	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19386570, 21404117, 22395473, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000945938

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 21, 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

[Our experience with the incidence of hereditary non-polyposis colorectal cancer].

Tanyi M.

Magy Seb. 2009 Apr;62(2):87-94. doi: 10.1556/MaSeb.62.2009.2.7. Hungarian.

PubMed [citation]

PMID:: 19386570

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000945938.5

#	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 glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 48 of the MLH1 protein (p.Gln48Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 479672). 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 not expected to disrupt MLH1 protein function. This variant disrupts the p.Gln48 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19386570, 21404117, 22395473, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Aug 11, 2024

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