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NM_000249.4(MLH1):c.121G>C (p.Asp41His) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 13, 2016
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:
RCV000255808.1

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)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000321893GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Pathogenic
(Jun 13, 2016) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000321893.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This pathogenic variant is denoted MLH1 c.121G>C at the cDNA level, p.Asp41His (D41H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been observed in several individuals with a history of colorectal cancer and has been shown to segregate with disease in a Spanish family meeting Amsterdam I criteria (Parc 2003, Bonnet 2012, Hinrichsen 2015, Pineda 2015). Both Pineda et al. (2015) and Bonnet et al. (2012) report that colorectal tumors from individuals found to harbor MLH1 Asp41His have been shown to be microsatellite unstable with retention of all four proteins via mismatch repair immunohistochemistry; however, it has been suggested that the retention of MLH1 in these tumors is due to a stable MLH1 protein that is catalytically inactive (Pineda 2015). Importantly, MLH1 Asp41His has been shown to result in greatly reduced mismatch repair activity in two separate in vitro based functional assays (Hinrichsen 2015, Pineda 2015). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asp41His occurs at a position that is conserved across species and is located within a region responsible for ATP-binding and hydrolysis (Raevaara 2005, Hardt 2011). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.

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

Last Updated: Sep 29, 2024