NM_000249.4(MLH1):c.121G>A (p.Asp41Asn) 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:: Aug 27, 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:: RCV001980735.3

Allele description

NM_000249.4(MLH1):c.121G>A (p.Asp41Asn)

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>A (p.Asp41Asn)

HGVS:

NC_000003.12:g.36996623G>A
NG_007109.2:g.8274G>A
NG_008418.1:g.1682C>T
NM_000249.4:c.121G>AMANE SELECT
NM_001167617.3:c.-169G>A
NM_001167618.3:c.-602-1G>A
NM_001167619.3:c.-511G>A
NM_001258271.2:c.121G>A
NM_001258273.2:c.-517+2960G>A
NM_001258274.3:c.-748G>A
NM_001354615.2:c.-506G>A
NM_001354616.2:c.-510-1G>A
NM_001354617.2:c.-602-1G>A
NM_001354618.2:c.-603G>A
NM_001354619.2:c.-603G>A
NM_001354620.2:c.-168-1G>A
NM_001354621.2:c.-696G>A
NM_001354622.2:c.-809G>A
NM_001354623.2:c.-723+2733G>A
NM_001354624.2:c.-706G>A
NM_001354625.2:c.-608-1G>A
NM_001354626.2:c.-705-1G>A
NM_001354627.2:c.-706G>A
NM_001354628.2:c.121G>A
NM_001354629.2:c.121G>A
NM_001354630.2:c.121G>A
NP_000240.1:p.Asp41Asn
NP_000240.1:p.Asp41Asn
NP_001245200.1:p.Asp41Asn
NP_001341557.1:p.Asp41Asn
NP_001341558.1:p.Asp41Asn
NP_001341559.1:p.Asp41Asn
LRG_216t1:c.121G>A
LRG_216:g.8274G>A
LRG_216p1:p.Asp41Asn
NC_000003.11:g.37038114G>A
NM_000249.3:c.121G>A

Protein change:

D41N

Links:

dbSNP: rs267607713

NCBI 1000 Genomes Browser:

rs267607713

Molecular consequence:

NM_001167617.3:c.-169G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-511G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-748G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-506G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-603G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-603G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-696G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-809G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-706G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-706G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2960G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2733G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.-602-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354616.2:c.-510-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354617.2:c.-602-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354620.2:c.-168-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354625.2:c.-608-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354626.2:c.-705-1G>A - 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
SCV002271431	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 27, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12624141, 15300854, 15365996, 19419416, 22480969, 22949387, 23403630, 24362816, 25060679, 25477341, 30998989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002271431

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 27, 2023)

germline

clinical testing

PubMed (12)
[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

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

RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1.

Sharp A, Pichert G, Lucassen A, Eccles D.

Hum Mutat. 2004 Sep;24(3):272.

PubMed [citation]

PMID:: 15300854

See all PubMed Citations (12)

Details of each submission

From Invitae, SCV002271431.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

ClinVar contains an entry for this variant (Variation ID: 1489661). 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.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 15300854, 15365996, 19419416, 22480969, 22949387, 23403630, 24362816, 25060679, 25477341, 30998989). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. RNA analysis provides insufficient evidence to determine the effect of this variant on MLH1 splicing (Invitae). 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 variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 41 of the MLH1 protein (p.Asp41Asn).

#	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: Feb 28, 2024

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