NM_000249.4(MLH1):c.2250_2251del (p.Tyr750_Lys751delinsTer) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 13, 2019
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:: RCV002428458.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2250_2251del (p.Tyr750_Lys751delinsTer)]

NM_000249.4(MLH1):c.2250_2251del (p.Tyr750_Lys751delinsTer)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2250_2251del (p.Tyr750_Lys751delinsTer)

HGVS:

NC_000003.12:g.37050632_37050633del
NG_007109.2:g.62283_62284del
NG_053016.1:g.131186_131187del
NM_000249.4:c.2250_2251delMANE SELECT
NM_001167617.3:c.1956_1957del
NM_001167618.3:c.1527_1528del
NM_001167619.3:c.1527_1528del
NM_001258271.2:c.2043_2044del
NM_001258273.2:c.1527_1528del
NM_001258274.3:c.1527_1528del
NM_001354615.2:c.1527_1528del
NM_001354616.2:c.1527_1528del
NM_001354617.2:c.1527_1528del
NM_001354618.2:c.1527_1528del
NM_001354619.2:c.1527_1528del
NM_001354620.2:c.1956_1957del
NM_001354621.2:c.1227_1228del
NM_001354622.2:c.1227_1228del
NM_001354623.2:c.1227_1228del
NM_001354624.2:c.1176_1177del
NM_001354625.2:c.1176_1177del
NM_001354626.2:c.1176_1177del
NM_001354627.2:c.1176_1177del
NM_001354628.2:c.2157_2158del
NM_001354629.2:c.2151_2152del
NM_001354630.2:c.2085_2086del
NP_000240.1:p.Tyr750Terfs
NP_000240.1:p.Tyr750_Lys751delinsTer
NP_001161089.1:p.Tyr652_Lys653delinsTer
NP_001161090.1:p.Tyr509_Lys510delinsTer
NP_001161091.1:p.Tyr509_Lys510delinsTer
NP_001245200.1:p.Tyr681_Lys682delinsTer
NP_001245202.1:p.Tyr509_Lys510delinsTer
NP_001245203.1:p.Tyr509_Lys510delinsTer
NP_001341544.1:p.Tyr509_Lys510delinsTer
NP_001341545.1:p.Tyr509_Lys510delinsTer
NP_001341546.1:p.Tyr509_Lys510delinsTer
NP_001341547.1:p.Tyr509_Lys510delinsTer
NP_001341548.1:p.Tyr509_Lys510delinsTer
NP_001341549.1:p.Tyr652_Lys653delinsTer
NP_001341550.1:p.Tyr409_Lys410delinsTer
NP_001341551.1:p.Tyr409_Lys410delinsTer
NP_001341552.1:p.Tyr409_Lys410delinsTer
NP_001341553.1:p.Tyr392_Lys393delinsTer
NP_001341554.1:p.Tyr392_Lys393delinsTer
NP_001341555.1:p.Tyr392_Lys393delinsTer
NP_001341556.1:p.Tyr392_Lys393delinsTer
NP_001341557.1:p.Tyr719_Lys720delinsTer
NP_001341558.1:p.Tyr717_Lys718delinsTer
NP_001341559.1:p.Tyr695_Lys696delinsTer
LRG_216t1:c.2250_2251del
LRG_216:g.62283_62284del
LRG_216p1:p.Tyr750Terfs
NC_000003.11:g.37092123_37092124del
NM_000249.3:c.2250_2251delCA

Molecular consequence:

NM_000249.4:c.2250_2251del - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1956_1957del - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.2043_2044del - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1527_1528del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1956_1957del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1227_1228del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1227_1228del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1227_1228del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1176_1177del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1176_1177del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1176_1177del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1176_1177del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.2157_2158del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.2151_2152del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.2085_2086del - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002728908	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 13, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10422993, 15613555, 16338176, 19690142, 20533529, 28767177, 28767289 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002728908

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 13, 2019)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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

Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.

Syngal S, Fox EA, Li C, Dovidio M, Eng C, Kolodner RD, Garber JE.

JAMA. 1999 Jul 21;282(3):247-53.

PubMed [citation]

PMID:: 10422993

Genetic characterization of Chinese hereditary non-polyposis colorectal cancer by DHPLC and multiplex PCR.

Yuan Y, Huang YQ, Cai SR, Song YM, Zheng S, Zhang SZ.

Jpn J Clin Oncol. 2004 Nov;34(11):660-6.

PubMed [citation]

PMID:: 15613555

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002728908.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The c.2250_2251delCA variant, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2250 to 2251, causing a translational frameshift with a predicted alternate stop codon (p.Y750*). The p.Y750* variant has been reported in individuals meeting Amsterdam I and Amsterdam II criteria, although the exact nucleotide variation for both was c.2250C>G (Syngal S et al. JAMA, 1999 Jul;282:247-53; Yuan Y et al. Jpn. J. Clin. Oncol., 2004 Nov;34:660-6). Premature stop codons are typically deleterious in nature; however, this stop codon, which occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay. Internal structural analysis suggests that the truncated region is critical for protein function since it contains the C-terminal Cys that coordinates binding of zinc needed for PMS2 endonuclease activity and contains part of the CTH domain which lies in the interaction domain with PMS2 and has been reported to be involved in PMS2 stabilization (Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: May 1, 2024

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