NM_000249.4(MLH1):c.2250C>G (p.Tyr750Ter) AND Lynch syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 21, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075585.3

Allele description [Variation Report for NM_000249.4(MLH1):c.2250C>G (p.Tyr750Ter)]

NM_000249.4(MLH1):c.2250C>G (p.Tyr750Ter)

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.2250C>G (p.Tyr750Ter)

HGVS:

NC_000003.12:g.37050632C>G
NG_007109.2:g.62283C>G
NG_053016.1:g.131186G>C
NM_000249.4:c.2250C>GMANE SELECT
NM_001167617.3:c.1956C>G
NM_001167618.3:c.1527C>G
NM_001167619.3:c.1527C>G
NM_001258271.2:c.2043C>G
NM_001258273.2:c.1527C>G
NM_001258274.3:c.1527C>G
NM_001354615.2:c.1527C>G
NM_001354616.2:c.1527C>G
NM_001354617.2:c.1527C>G
NM_001354618.2:c.1527C>G
NM_001354619.2:c.1527C>G
NM_001354620.2:c.1956C>G
NM_001354621.2:c.1227C>G
NM_001354622.2:c.1227C>G
NM_001354623.2:c.1227C>G
NM_001354624.2:c.1176C>G
NM_001354625.2:c.1176C>G
NM_001354626.2:c.1176C>G
NM_001354627.2:c.1176C>G
NM_001354628.2:c.2157C>G
NM_001354629.2:c.2151C>G
NM_001354630.2:c.2085C>G
NP_000240.1:p.Tyr750Ter
NP_000240.1:p.Tyr750Ter
NP_001161089.1:p.Tyr652Ter
NP_001161090.1:p.Tyr509Ter
NP_001161091.1:p.Tyr509Ter
NP_001245200.1:p.Tyr681Ter
NP_001245202.1:p.Tyr509Ter
NP_001245203.1:p.Tyr509Ter
NP_001341544.1:p.Tyr509Ter
NP_001341545.1:p.Tyr509Ter
NP_001341546.1:p.Tyr509Ter
NP_001341547.1:p.Tyr509Ter
NP_001341548.1:p.Tyr509Ter
NP_001341549.1:p.Tyr652Ter
NP_001341550.1:p.Tyr409Ter
NP_001341551.1:p.Tyr409Ter
NP_001341552.1:p.Tyr409Ter
NP_001341553.1:p.Tyr392Ter
NP_001341554.1:p.Tyr392Ter
NP_001341555.1:p.Tyr392Ter
NP_001341556.1:p.Tyr392Ter
NP_001341557.1:p.Tyr719Ter
NP_001341558.1:p.Tyr717Ter
NP_001341559.1:p.Tyr695Ter
LRG_216t1:c.2250C>G
LRG_216:g.62283C>G
LRG_216p1:p.Tyr750Ter
NC_000003.11:g.37092123C>G
NM_000249.3:c.2250C>G
p.Tyr750*

Protein change:

Y392*

Links:

dbSNP: rs267607893

NCBI 1000 Genomes Browser:

rs267607893

Molecular consequence:

NM_000249.4:c.2250C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1956C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.2043C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1527C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1956C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1227C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1227C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1227C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1176C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1176C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1176C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1176C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.2157C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.2151C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.2085C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106582	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Uncertain significance (Jun 21, 2019)	germline	curation	Citation Link,
SCV000592446	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 5, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20533529, 16338176, 19690142, 11369138, 10422993, 16810763, 15613555, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106582

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Uncertain significance
(Jun 21, 2019)

germline

curation

Citation Link,

SCV000592446

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 5, 2016)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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, curation

Citations

PubMed

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

Kosinski J, Hinrichsen I, Bujnicki JM, Friedhoff P, Plotz G.

Hum Mutat. 2010 Aug;31(8):975-82. doi: 10.1002/humu.21301.

PubMed [citation]

PMID:: 20533529
PMCID:: PMC2908215

Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair.

Mohd AB, Palama B, Nelson SE, Tomer G, Nguyen M, Huo X, Buermeyer AB.

DNA Repair (Amst). 2006 Mar 7;5(3):347-61. Epub 2005 Dec 9.

PubMed [citation]

PMID:: 16338176

See all PubMed Citations (8)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106582.3

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

Description

Insufficient evidence: premature termination codon outside of known functional domain; Nonsense variant after codon 743 in MLH1 = VUS

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592446.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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: May 1, 2024

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