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NM_000249.4(MLH1):c.122A>T (p.Asp41Val) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 18, 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:
RCV000553834.7

Allele description [Variation Report for NM_000249.4(MLH1):c.122A>T (p.Asp41Val)]

NM_000249.4(MLH1):c.122A>T (p.Asp41Val)

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.122A>T (p.Asp41Val)
HGVS:
  • NC_000003.12:g.36996624A>T
  • NG_007109.2:g.8275A>T
  • NG_008418.1:g.1681T>A
  • NM_000249.4:c.122A>TMANE SELECT
  • NM_001167617.3:c.-168A>T
  • NM_001167618.3:c.-602A>T
  • NM_001167619.3:c.-510A>T
  • NM_001258271.2:c.122A>T
  • NM_001258273.2:c.-517+2961A>T
  • NM_001258274.3:c.-747A>T
  • NM_001354615.2:c.-505A>T
  • NM_001354616.2:c.-510A>T
  • NM_001354617.2:c.-602A>T
  • NM_001354618.2:c.-602A>T
  • NM_001354619.2:c.-602A>T
  • NM_001354620.2:c.-168A>T
  • NM_001354621.2:c.-695A>T
  • NM_001354622.2:c.-808A>T
  • NM_001354623.2:c.-723+2734A>T
  • NM_001354624.2:c.-705A>T
  • NM_001354625.2:c.-608A>T
  • NM_001354626.2:c.-705A>T
  • NM_001354627.2:c.-705A>T
  • NM_001354628.2:c.122A>T
  • NM_001354629.2:c.122A>T
  • NM_001354630.2:c.122A>T
  • NP_000240.1:p.Asp41Val
  • NP_000240.1:p.Asp41Val
  • NP_001245200.1:p.Asp41Val
  • NP_001341557.1:p.Asp41Val
  • NP_001341558.1:p.Asp41Val
  • NP_001341559.1:p.Asp41Val
  • LRG_216t1:c.122A>T
  • LRG_216:g.8275A>T
  • LRG_216p1:p.Asp41Val
  • NC_000003.11:g.37038115A>T
  • NM_000249.3:c.122A>T
Protein change:
D41V
Links:
dbSNP: rs63751094
NCBI 1000 Genomes Browser:
rs63751094
Molecular consequence:
  • NM_001167617.3:c.-168A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-602A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-510A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-747A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-505A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-510A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-602A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-602A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-602A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-168A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-695A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-808A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-705A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-608A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-705A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-705A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-517+2961A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-723+2734A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.122A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.122A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.122A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.122A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.122A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000625050Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 18, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625050.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 41 of the MLH1 protein (p.Asp41Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 19419416; Invitae). ClinVar contains an entry for this variant (Variation ID: 455379). 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 disrupts the p.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 25060679, 25477341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024