NM_000249.4(MLH1):c.2172del (p.Leu724fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 16, 2018
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:: RCV002432758.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2172del (p.Leu724fs)]

NM_000249.4(MLH1):c.2172del (p.Leu724fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2172del (p.Leu724fs)

HGVS:

NC_000003.12:g.37050554del
NG_007109.2:g.62205del
NM_000249.4:c.2172delMANE SELECT
NM_001167617.3:c.1878del
NM_001167618.3:c.1449del
NM_001167619.3:c.1449del
NM_001258271.2:c.1965del
NM_001258273.2:c.1449del
NM_001258274.3:c.1449del
NM_001354615.2:c.1449del
NM_001354616.2:c.1449del
NM_001354617.2:c.1449del
NM_001354618.2:c.1449del
NM_001354619.2:c.1449del
NM_001354620.2:c.1878del
NM_001354621.2:c.1149del
NM_001354622.2:c.1149del
NM_001354623.2:c.1149del
NM_001354624.2:c.1098del
NM_001354625.2:c.1098del
NM_001354626.2:c.1098del
NM_001354627.2:c.1098del
NM_001354628.2:c.2079del
NM_001354629.2:c.2073del
NM_001354630.2:c.2007del
NP_000240.1:p.Leu724Phefs
NP_000240.1:p.Leu724fs
NP_001161089.1:p.Leu626fs
NP_001161090.1:p.Leu483fs
NP_001161091.1:p.Leu483fs
NP_001245200.1:p.Leu655fs
NP_001245202.1:p.Leu483fs
NP_001245203.1:p.Leu483fs
NP_001341544.1:p.Leu483fs
NP_001341545.1:p.Leu483fs
NP_001341546.1:p.Leu483fs
NP_001341547.1:p.Leu483fs
NP_001341548.1:p.Leu483fs
NP_001341549.1:p.Leu626fs
NP_001341550.1:p.Leu383fs
NP_001341551.1:p.Leu383fs
NP_001341552.1:p.Leu383fs
NP_001341553.1:p.Leu366fs
NP_001341554.1:p.Leu366fs
NP_001341555.1:p.Leu366fs
NP_001341556.1:p.Leu366fs
NP_001341557.1:p.Leu693fs
NP_001341558.1:p.Leu691fs
NP_001341559.1:p.Leu669fs
LRG_216t1:c.2172del
LRG_216:g.62205del
LRG_216p1:p.Leu724Phefs
NC_000003.11:g.37092045del
NM_000249.3:c.2172delG

Protein change:

L366fs

Molecular consequence:

NM_000249.4:c.2172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1878del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1965del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1878del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1098del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1098del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1098del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1098del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2079del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2073del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2007del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

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SRX19576659 (1)
SRA
Chain h, Small nuclear ribonucleoprotein Sm D3
Chain h, Small nuclear ribonucleoprotein Sm D3
gi|1938953273|pdb|5Z57|h

Protein
Sequence 117 from Patent WO2009043908
Sequence 117 from Patent WO2009043908
gi|229617554|emb|GN344137.1||pat|WO 043908|117

Nucleotide
DA709639 NT2RI2 Homo sapiens cDNA clone NT2RI2014936 5', mRNA sequence
DA709639 NT2RI2 Homo sapiens cDNA clone NT2RI2014936 5', mRNA sequence
gi|82419364|gnl|dbEST|33857300|dbj| 639.1|

Nucleotide
Septoria pistaciarum strain CBS 135838 RNA polymerase II subunit (RPB2) gene, pa...
Septoria pistaciarum strain CBS 135838 RNA polymerase II subunit (RPB2) gene, partial cds
gi|537099963|gb|KF442728.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002731407	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 16, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002731407

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 16, 2018)

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, SCV002731407.2

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

Description

The c.2172delG variant, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2172, causing a translational frameshift with a predicted alternate stop codon (p.L724Ffs*59). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of MLH1 , is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 25 amino acids. Structural analysis shows that this alteration perturbs a known functional domain responsible for binding to PMS2 and removes a cysteine residue shown to be involved in metal binding as part of a functional domain in PMS2 (Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61; Smith CE et al. PLoS Genet. 2013 Oct;9(10):e1003869). 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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