NM_000249.4(MLH1):c.2250C>A (p.Tyr750Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 10, 2021
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:: RCV001854299.4

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

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

HGVS:

NC_000003.12:g.37050632C>A
NG_007109.2:g.62283C>A
NG_053016.1:g.131186G>T
NM_000249.4:c.2250C>AMANE SELECT
NM_001167617.3:c.1956C>A
NM_001167618.3:c.1527C>A
NM_001167619.3:c.1527C>A
NM_001258271.2:c.2043C>A
NM_001258273.2:c.1527C>A
NM_001258274.3:c.1527C>A
NM_001354615.2:c.1527C>A
NM_001354616.2:c.1527C>A
NM_001354617.2:c.1527C>A
NM_001354618.2:c.1527C>A
NM_001354619.2:c.1527C>A
NM_001354620.2:c.1956C>A
NM_001354621.2:c.1227C>A
NM_001354622.2:c.1227C>A
NM_001354623.2:c.1227C>A
NM_001354624.2:c.1176C>A
NM_001354625.2:c.1176C>A
NM_001354626.2:c.1176C>A
NM_001354627.2:c.1176C>A
NM_001354628.2:c.2157C>A
NM_001354629.2:c.2151C>A
NM_001354630.2:c.2085C>A
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>A
LRG_216:g.62283C>A
LRG_216p1:p.Tyr750Ter
NC_000003.11:g.37092123C>A
NM_000249.3:c.2250C>A

Protein change:

Y392*

Links:

dbSNP: rs267607893

NCBI 1000 Genomes Browser:

rs267607893

Molecular consequence:

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

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002229931	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 10, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8797773, 18566915, 18931482, 24802709, 27295708, 20533529, 20233461, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002229931

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 10, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer.

Han HJ, Yuan Y, Ku JL, Oh JH, Won YJ, Kang KJ, Kim KY, Kim S, Kim CY, Kim JP, Oh NG, Lee KH, Choe KJ, Nakamura Y, Park JG.

J Natl Cancer Inst. 1996 Sep 18;88(18):1317-9. No abstract available.

PubMed [citation]

PMID:: 8797773

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002229931.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects MLH1 function (PMID: 20533529). ClinVar contains an entry for this variant (Variation ID: 90098). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20233461). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr750*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the MLH1 protein.

#	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: Sep 29, 2024

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