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NM_000249.4(MLH1):c.122A>T (p.Asp41Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 14, 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:
RCV000571853.4

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 cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000673820Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 14, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.

Zhu M, Chen HM, Wang YP.

Oncol Lett. 2013 May;5(5):1710-1718. Epub 2013 Mar 11.

PubMed [citation]
PMID:
23760103
PMCID:
PMC3678577
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000673820.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The p.D41V pathogenic mutation (also known as c.122A>T), located in coding exon 2 of the MLH1 gene, results from an A to T substitution at nucleotide position 122. The aspartic acid at codon 41 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been detected in multiple families meeting Amsterdam I criteria (Ambry internal data). Based on internal structural analysis, p.D41V is structurally deleterious (Ambry internal data; Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). An alteration resulting in the same amino acid change, p.D41V (c.122_123delATinsTA) has been reported in 1 of 93 unrelated Taiwanese families that fulfilled the Amsterdam II criteria with concordant MSI and/or IHC, and was not found in 300 controls (Tang R et al, Clin. Genet. 2009 Apr; 75(4):334-45). Further, an alteration at the same codon, p.D41G (c.122A>G) has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024