NM_000249.4(MLH1):c.2135G>A (p.Trp712Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 1, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000202047.9

Allele description [Variation Report for NM_000249.4(MLH1):c.2135G>A (p.Trp712Ter)]

NM_000249.4(MLH1):c.2135G>A (p.Trp712Ter)

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.2135G>A (p.Trp712Ter)

HGVS:

NC_000003.12:g.37050517G>A
NG_007109.2:g.62168G>A
NM_000249.4:c.2135G>AMANE SELECT
NM_001167617.3:c.1841G>A
NM_001167618.3:c.1412G>A
NM_001167619.3:c.1412G>A
NM_001258271.2:c.1928G>A
NM_001258273.2:c.1412G>A
NM_001258274.3:c.1412G>A
NM_001354615.2:c.1412G>A
NM_001354616.2:c.1412G>A
NM_001354617.2:c.1412G>A
NM_001354618.2:c.1412G>A
NM_001354619.2:c.1412G>A
NM_001354620.2:c.1841G>A
NM_001354621.2:c.1112G>A
NM_001354622.2:c.1112G>A
NM_001354623.2:c.1112G>A
NM_001354624.2:c.1061G>A
NM_001354625.2:c.1061G>A
NM_001354626.2:c.1061G>A
NM_001354627.2:c.1061G>A
NM_001354628.2:c.2042G>A
NM_001354629.2:c.2036G>A
NM_001354630.2:c.1970G>A
NP_000240.1:p.Trp712Ter
NP_000240.1:p.Trp712Ter
NP_001161089.1:p.Trp614Ter
NP_001161090.1:p.Trp471Ter
NP_001161091.1:p.Trp471Ter
NP_001245200.1:p.Trp643Ter
NP_001245202.1:p.Trp471Ter
NP_001245203.1:p.Trp471Ter
NP_001341544.1:p.Trp471Ter
NP_001341545.1:p.Trp471Ter
NP_001341546.1:p.Trp471Ter
NP_001341547.1:p.Trp471Ter
NP_001341548.1:p.Trp471Ter
NP_001341549.1:p.Trp614Ter
NP_001341550.1:p.Trp371Ter
NP_001341551.1:p.Trp371Ter
NP_001341552.1:p.Trp371Ter
NP_001341553.1:p.Trp354Ter
NP_001341554.1:p.Trp354Ter
NP_001341555.1:p.Trp354Ter
NP_001341556.1:p.Trp354Ter
NP_001341557.1:p.Trp681Ter
NP_001341558.1:p.Trp679Ter
NP_001341559.1:p.Trp657Ter
LRG_216t1:c.2135G>A
LRG_216:g.62168G>A
LRG_216p1:p.Trp712Ter
NC_000003.11:g.37092008G>A
NM_000249.3:c.2135G>A

Protein change:

W354*

Links:

dbSNP: rs63750561

NCBI 1000 Genomes Browser:

rs63750561

Molecular consequence:

NM_000249.4:c.2135G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1841G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.1928G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1412G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1841G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1112G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1112G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1112G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1061G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1061G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1061G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1061G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.2042G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.2036G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.1970G>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
SCV000257087	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	research
SCV001772661	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 1, 2019)	germline	clinical testing	Citation Link,
SCV002017493	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 15, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000257087

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Pathogenic

unknown

research

SCV001772661

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 1, 2019)

germline

clinical testing

Citation Link,

SCV002017493

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 15, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257087.1

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

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

From GeneDx, SCV001772661.1

#	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 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and the published literature (Kondo 2003, Mohd 2006, Kosinski 2010, Stenson 2014); Published functional studies demonstrate a damaging effect: variant impairs PMS2 and EXO1 binding (Kondo 2003); Observed in individuals with HNPCC-associated cancers (Liu 1996, Coleman 2001, Kondo 2003, Pigatto 2004); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27978560, 26666765, 15555211, 20233461, 15855432, 12624141, 10422993, 16338176, 20533529, 12810663, 8574961, 11720433)

#	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

From Revvity Omics, Revvity, SCV002017493.3

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

#	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: Apr 20, 2024

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