NM_000249.4(MLH1):c.121G>C (p.Asp41His) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 19, 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:: RCV003593875.2

Allele description [Variation Report for NM_000249.4(MLH1):c.121G>C (p.Asp41His)]

NM_000249.4(MLH1):c.121G>C (p.Asp41His)

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.121G>C (p.Asp41His)

HGVS:

NC_000003.12:g.36996623G>C
NG_007109.2:g.8274G>C
NG_008418.1:g.1682C>G
NM_000249.4:c.121G>CMANE SELECT
NM_001167617.3:c.-169G>C
NM_001167618.3:c.-602-1G>C
NM_001167619.3:c.-511G>C
NM_001258271.2:c.121G>C
NM_001258273.2:c.-517+2960G>C
NM_001258274.3:c.-748G>C
NM_001354615.2:c.-506G>C
NM_001354616.2:c.-510-1G>C
NM_001354617.2:c.-602-1G>C
NM_001354618.2:c.-603G>C
NM_001354619.2:c.-603G>C
NM_001354620.2:c.-168-1G>C
NM_001354621.2:c.-696G>C
NM_001354622.2:c.-809G>C
NM_001354623.2:c.-723+2733G>C
NM_001354624.2:c.-706G>C
NM_001354625.2:c.-608-1G>C
NM_001354626.2:c.-705-1G>C
NM_001354627.2:c.-706G>C
NM_001354628.2:c.121G>C
NM_001354629.2:c.121G>C
NM_001354630.2:c.121G>C
NP_000240.1:p.Asp41His
NP_000240.1:p.Asp41His
NP_001245200.1:p.Asp41His
NP_001341557.1:p.Asp41His
NP_001341558.1:p.Asp41His
NP_001341559.1:p.Asp41His
LRG_216t1:c.121G>C
LRG_216:g.8274G>C
LRG_216p1:p.Asp41His
NC_000003.11:g.37038114G>C
NM_000249.3:c.121G>C
P40692:p.Asp41His

Protein change:

D41H

Links:

UniProtKB: P40692#VAR_054522; dbSNP: rs267607713

NCBI 1000 Genomes Browser:

rs267607713

Molecular consequence:

NM_001167617.3:c.-169G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-511G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-748G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-506G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-603G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-603G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-696G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-809G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-706G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-706G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2960G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2733G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.-602-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354616.2:c.-510-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354617.2:c.-602-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354620.2:c.-168-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354625.2:c.-608-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354626.2:c.-705-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV004293447	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19419416, 12624141, 25060679, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004293447

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 19, 2023)

germline

clinical testing

PubMed (4)
[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

Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.

Tang R, Hsiung C, Wang JY, Lai CH, Chien HT, Chiu LL, Liu CT, Chen HH, Wang HM, Chen SX, Hsieh LL; TCOG HNPCC Consortium..

Clin Genet. 2009 Apr;75(4):334-45. doi: 10.1111/j.1399-0004.2009.01162.x.

PubMed [citation]

PMID:: 19419416

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004293447.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19419416). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects MLH1 function (PMID: 25060679). 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: 89682). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 12624141, 25060679). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 41 of the MLH1 protein (p.Asp41His).

#	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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