NM_000249.4(MLH1):c.1758dup (p.Met587fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 8, 2024
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:: RCV000573311.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1758dup (p.Met587fs)]

NM_000249.4(MLH1):c.1758dup (p.Met587fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1758dup (p.Met587fs)

HGVS:

NC_000003.12:g.37047545dup
NG_007109.2:g.59196dup
NM_000249.4:c.1758dupMANE SELECT
NM_001167617.3:c.1464dup
NM_001167618.3:c.1035dup
NM_001167619.3:c.1035dup
NM_001258271.2:c.1758dup
NM_001258273.2:c.1035dup
NM_001258274.3:c.1035dup
NM_001354615.2:c.1035dup
NM_001354616.2:c.1035dup
NM_001354617.2:c.1035dup
NM_001354618.2:c.1035dup
NM_001354619.2:c.1035dup
NM_001354620.2:c.1464dup
NM_001354621.2:c.735dup
NM_001354622.2:c.735dup
NM_001354623.2:c.735dup
NM_001354624.2:c.684dup
NM_001354625.2:c.684dup
NM_001354626.2:c.684dup
NM_001354627.2:c.684dup
NM_001354628.2:c.1758dup
NM_001354629.2:c.1659dup
NM_001354630.2:c.1732-972dup
NP_000240.1:p.Met587fs
NP_001161089.1:p.Met489fs
NP_001161090.1:p.Met346fs
NP_001161091.1:p.Met346fs
NP_001245200.1:p.Met587fs
NP_001245202.1:p.Met346fs
NP_001245203.1:p.Met346fs
NP_001341544.1:p.Met346fs
NP_001341545.1:p.Met346fs
NP_001341546.1:p.Met346fs
NP_001341547.1:p.Met346fs
NP_001341548.1:p.Met346fs
NP_001341549.1:p.Met489fs
NP_001341550.1:p.Met246fs
NP_001341551.1:p.Met246fs
NP_001341552.1:p.Met246fs
NP_001341553.1:p.Met229fs
NP_001341554.1:p.Met229fs
NP_001341555.1:p.Met229fs
NP_001341556.1:p.Met229fs
NP_001341557.1:p.Met587fs
NP_001341558.1:p.Met554fs
LRG_216:g.59196dup
NC_000003.11:g.37089034_37089035insC
NC_000003.11:g.37089036dup
NM_000249.3:c.1758dupC

Protein change:

M229fs

Links:

dbSNP: rs63749863

NCBI 1000 Genomes Browser:

rs63749863

Molecular consequence:

NM_000249.4:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1464dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1464dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.1659dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.1732-972dup - intron variant - [Sequence Ontology: SO:0001627]

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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SRX18374603 (1)
SRA
UNVERIFIED: Peperomia lancifolia genomic sequence
UNVERIFIED: Peperomia lancifolia genomic sequence
gi|1343175562|gb|MF287626.1|

Nucleotide
Carex humilis voucher WYJ202008158 maturase K (matK) gene, partial cds; chloropl...
Carex humilis voucher WYJ202008158 maturase K (matK) gene, partial cds; chloroplast
gi|2426305160|gb|MW417769.1|

Nucleotide
PREDICTED: Momordica charantia uncharacterized LOC111004517 (LOC111004517), tran...
PREDICTED: Momordica charantia uncharacterized LOC111004517 (LOC111004517), transcript variant X1, mRNA
gi|1229757638|ref|XM_022275569.1|

Nucleotide
uncharacterized protein LOC111004517 [Momordica charantia]
uncharacterized protein LOC111004517 [Momordica charantia]
gi|1229757641|ref|XP_022131262.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000676035	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 8, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000676035

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 8, 2024)

germline

clinical testing

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

Details of each submission

From Ambry Genetics, SCV000676035.5

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

Description

The c.1758dupC pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a duplication of C at nucleotide position 1758, causing a translational frameshift with a predicted alternate stop codon (p.M587Hfs*6). This variant was reported in multiple Korean individuals with features consistent with Lynch syndrome (Han et al. Hum. Mol. Genet. 1995; 4(2)237-42; Shin et al. Hum. Mutat. 2004;24(4):351; Wei et al. J. Bioinform. Comput. Biol. 2010; 8(Suppl. 1):111-25; Shin et al. Obstet Gynecol. Sci. 2015; 58(2):112-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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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