NM_000249.4(MLH1):c.2221del (p.Leu741fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 17, 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:: RCV002420124.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2221del (p.Leu741fs)]

NM_000249.4(MLH1):c.2221del (p.Leu741fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2221del (p.Leu741fs)

HGVS:

NC_000003.12:g.37050603del
NG_007109.2:g.62254del
NM_000249.4:c.2221delMANE SELECT
NM_001167617.3:c.1927del
NM_001167618.3:c.1498del
NM_001167619.3:c.1498del
NM_001258271.2:c.2014del
NM_001258273.2:c.1498del
NM_001258274.3:c.1498del
NM_001354615.2:c.1498del
NM_001354616.2:c.1498del
NM_001354617.2:c.1498del
NM_001354618.2:c.1498del
NM_001354619.2:c.1498del
NM_001354620.2:c.1927del
NM_001354621.2:c.1198del
NM_001354622.2:c.1198del
NM_001354623.2:c.1198del
NM_001354624.2:c.1147del
NM_001354625.2:c.1147del
NM_001354626.2:c.1147del
NM_001354627.2:c.1147del
NM_001354628.2:c.2128del
NM_001354629.2:c.2122del
NM_001354630.2:c.2056del
NP_000240.1:p.Leu741Cysfs
NP_000240.1:p.Leu741fs
NP_001161089.1:p.Leu643fs
NP_001161090.1:p.Leu500fs
NP_001161091.1:p.Leu500fs
NP_001245200.1:p.Leu672fs
NP_001245202.1:p.Leu500fs
NP_001245203.1:p.Leu500fs
NP_001341544.1:p.Leu500fs
NP_001341545.1:p.Leu500fs
NP_001341546.1:p.Leu500fs
NP_001341547.1:p.Leu500fs
NP_001341548.1:p.Leu500fs
NP_001341549.1:p.Leu643fs
NP_001341550.1:p.Leu400fs
NP_001341551.1:p.Leu400fs
NP_001341552.1:p.Leu400fs
NP_001341553.1:p.Leu383fs
NP_001341554.1:p.Leu383fs
NP_001341555.1:p.Leu383fs
NP_001341556.1:p.Leu383fs
NP_001341557.1:p.Leu710fs
NP_001341558.1:p.Leu708fs
NP_001341559.1:p.Leu686fs
LRG_216t1:c.2221del
LRG_216:g.62254del
LRG_216p1:p.Leu741Cysfs
NC_000003.11:g.37092093del
NC_000003.11:g.37092094del
NM_000249.3:c.2221delC

Protein change:

L383fs

Molecular consequence:

NM_000249.4:c.2221del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1927del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.2014del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1927del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2128del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2122del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2056del - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002724894	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 17, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002724894

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 17, 2019)

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, SCV002724894.2

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

Description

The c.2221delC variant, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2221, causing a translational frameshift with a predicted alternate stop codon (p.L741Cfs*42). 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. The exact functional impact of these inserted amino acids is unknown at this time. 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: Sep 29, 2024

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