NM_000249.4(MLH1):c.2141G>A (p.Trp714Ter) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 26, 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:: RCV002280100.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2141G>A (p.Trp714Ter)]

NM_000249.4(MLH1):c.2141G>A (p.Trp714Ter)

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.2141G>A (p.Trp714Ter)

HGVS:

NC_000003.12:g.37050523G>A
NG_007109.2:g.62174G>A
NM_000249.4:c.2141G>AMANE SELECT
NM_001167617.3:c.1847G>A
NM_001167618.3:c.1418G>A
NM_001167619.3:c.1418G>A
NM_001258271.2:c.1934G>A
NM_001258273.2:c.1418G>A
NM_001258274.3:c.1418G>A
NM_001354615.2:c.1418G>A
NM_001354616.2:c.1418G>A
NM_001354617.2:c.1418G>A
NM_001354618.2:c.1418G>A
NM_001354619.2:c.1418G>A
NM_001354620.2:c.1847G>A
NM_001354621.2:c.1118G>A
NM_001354622.2:c.1118G>A
NM_001354623.2:c.1118G>A
NM_001354624.2:c.1067G>A
NM_001354625.2:c.1067G>A
NM_001354626.2:c.1067G>A
NM_001354627.2:c.1067G>A
NM_001354628.2:c.2048G>A
NM_001354629.2:c.2042G>A
NM_001354630.2:c.1976G>A
NP_000240.1:p.Trp714Ter
NP_000240.1:p.Trp714Ter
NP_001161089.1:p.Trp616Ter
NP_001161090.1:p.Trp473Ter
NP_001161091.1:p.Trp473Ter
NP_001245200.1:p.Trp645Ter
NP_001245202.1:p.Trp473Ter
NP_001245203.1:p.Trp473Ter
NP_001341544.1:p.Trp473Ter
NP_001341545.1:p.Trp473Ter
NP_001341546.1:p.Trp473Ter
NP_001341547.1:p.Trp473Ter
NP_001341548.1:p.Trp473Ter
NP_001341549.1:p.Trp616Ter
NP_001341550.1:p.Trp373Ter
NP_001341551.1:p.Trp373Ter
NP_001341552.1:p.Trp373Ter
NP_001341553.1:p.Trp356Ter
NP_001341554.1:p.Trp356Ter
NP_001341555.1:p.Trp356Ter
NP_001341556.1:p.Trp356Ter
NP_001341557.1:p.Trp683Ter
NP_001341558.1:p.Trp681Ter
NP_001341559.1:p.Trp659Ter
LRG_216t1:c.2141G>A
LRG_216:g.62174G>A
LRG_216p1:p.Trp714Ter
NC_000003.11:g.37092014G>A
NM_000249.3:c.2141G>A
p.W714*

Protein change:

W356*

Links:

dbSNP: rs63751022

NCBI 1000 Genomes Browser:

rs63751022

Molecular consequence:

NM_000249.4:c.2141G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1847G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.1934G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1418G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1847G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1118G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1118G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1118G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1067G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1067G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1067G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1067G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.2048G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.2042G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.1976G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002568555	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 26, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002568555

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 26, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV002568555.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 43 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Observed in several unrelated patients from different ethnic backgrounds with Lynch-related cancers in published literature, some of which showing tumor studies consistent with pathogenic variants in this gene (Froggatt 1996, Kondo 2003, Sheng 2006, Bonadona 2011, Martin-Morales 2018); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: inability to induce dominant mutator effect, loss of mismatch repair activity, and decreased protein expression (Shimodaira 1998, Takahashi 2007); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); This variant is associated with the following publications: (PMID: 8863153, 25504677, 12810663, 30256826, 19931546, 25345868, 27601186, 15322516, 11093816, 8880570, 28514183, 17510385, 9697702, 17054581, 21642682, 23640085, 31830689, 9833759)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine