NM_000249.4(MLH1):c.1772_1775del (p.Asp591fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 9, 2023
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:: RCV000202011.12

Allele description [Variation Report for NM_000249.4(MLH1):c.1772_1775del (p.Asp591fs)]

NM_000249.4(MLH1):c.1772_1775del (p.Asp591fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1772_1775del (p.Asp591fs)

HGVS:

NC_000003.12:g.37047559_37047562del
NG_007109.2:g.59210_59213del
NM_000249.4:c.1772_1775delMANE SELECT
NM_001167617.3:c.1478_1481del
NM_001167618.3:c.1049_1052del
NM_001167619.3:c.1049_1052del
NM_001258271.2:c.1772_1775del
NM_001258273.2:c.1049_1052del
NM_001258274.3:c.1049_1052del
NM_001354615.2:c.1049_1052del
NM_001354616.2:c.1049_1052del
NM_001354617.2:c.1049_1052del
NM_001354618.2:c.1049_1052del
NM_001354619.2:c.1049_1052del
NM_001354620.2:c.1478_1481del
NM_001354621.2:c.749_752del
NM_001354622.2:c.749_752del
NM_001354623.2:c.749_752del
NM_001354624.2:c.698_701del
NM_001354625.2:c.698_701del
NM_001354626.2:c.698_701del
NM_001354627.2:c.698_701del
NM_001354628.2:c.1772_1775del
NM_001354629.2:c.1673_1676del
NM_001354630.2:c.1732-958_1732-955del
NP_000240.1:p.Asp591fs
NP_001161089.1:p.Asp493fs
NP_001161090.1:p.Asp350fs
NP_001161091.1:p.Asp350fs
NP_001245200.1:p.Asp591fs
NP_001245202.1:p.Asp350fs
NP_001245203.1:p.Asp350fs
NP_001341544.1:p.Asp350fs
NP_001341545.1:p.Asp350fs
NP_001341546.1:p.Asp350fs
NP_001341547.1:p.Asp350fs
NP_001341548.1:p.Asp350fs
NP_001341549.1:p.Asp493fs
NP_001341550.1:p.Asp250fs
NP_001341551.1:p.Asp250fs
NP_001341552.1:p.Asp250fs
NP_001341553.1:p.Asp233fs
NP_001341554.1:p.Asp233fs
NP_001341555.1:p.Asp233fs
NP_001341556.1:p.Asp233fs
NP_001341557.1:p.Asp591fs
NP_001341558.1:p.Asp558fs
LRG_216:g.59210_59213del
NC_000003.11:g.37089047_37089050del
NC_000003.11:g.37089050_37089053del
NM_000249.3:c.1772_1775delATAG
NM_000249.4:c.1772_1775del
p.Asp591Valfs*24

Protein change:

D233fs

Links:

dbSNP: rs63749868

NCBI 1000 Genomes Browser:

rs63749868

Molecular consequence:

NM_000249.4:c.1772_1775del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1478_1481del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1772_1775del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1049_1052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1478_1481del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.749_752del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.749_752del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.749_752del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.698_701del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.698_701del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.698_701del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.698_701del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.1772_1775del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.1673_1676del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.1732-958_1732-955del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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RecName: Full=Zinc finger protein 77; AltName: Full=ZNFpT1
RecName: Full=Zinc finger protein 77; AltName: Full=ZNFpT1
gi|85681869|sp|Q15935.2|ZNF77_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000257064	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	research
SCV000568567	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 9, 2023)	germline	clinical testing	Citation Link,
SCV000601367	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jul 28, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8872463, 12810663, 12362848, 17312306, 26467025
SCV001446920	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	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	unknown	unknown	1	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.

Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham JM, French AJ, Halling KC, Schwab M, Goretzki P, Thibodeau SN.

Hum Mol Genet. 1996 Sep;5(9):1245-52.

PubMed [citation]

PMID:: 8872463

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]

PMID:: 12810663

See all PubMed Citations (6)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257064.1

#	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, SCV000568567.8

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MLH1-related cancers (PMID: 26248088, 29228462); This variant is associated with the following publications: (PMID: 26248088, 8872463, 12810663, 29228462, 17312306)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601367.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446920.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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