NM_000249.4(MLH1):c.1017del (p.Ser340fs) AND Lynch syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075075.2

Allele description

NM_000249.4(MLH1):c.1017del (p.Ser340fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1017del (p.Ser340fs)

HGVS:

NC_000003.12:g.37020442del
NG_007109.2:g.32093del
NM_000249.4:c.1017delMANE SELECT
NM_001167617.3:c.723del
NM_001167618.3:c.294del
NM_001167619.3:c.294del
NM_001258271.2:c.1017del
NM_001258273.2:c.294del
NM_001258274.3:c.294del
NM_001354615.2:c.294del
NM_001354616.2:c.294del
NM_001354617.2:c.294del
NM_001354618.2:c.294del
NM_001354619.2:c.294del
NM_001354620.2:c.723del
NM_001354621.2:c.-7del
NM_001354622.2:c.-7del
NM_001354623.2:c.-7del
NM_001354624.2:c.-36-5195del
NM_001354625.2:c.-36-5195del
NM_001354626.2:c.-36-5195del
NM_001354627.2:c.-36-5195del
NM_001354628.2:c.1017del
NM_001354629.2:c.918del
NM_001354630.2:c.1017del
NP_000240.1:p.Ser340fs
NP_001161089.1:p.Ser242fs
NP_001161090.1:p.Ser99fs
NP_001161091.1:p.Ser99fs
NP_001245200.1:p.Ser340fs
NP_001245202.1:p.Ser99fs
NP_001245203.1:p.Ser99fs
NP_001341544.1:p.Ser99fs
NP_001341545.1:p.Ser99fs
NP_001341546.1:p.Ser99fs
NP_001341547.1:p.Ser99fs
NP_001341548.1:p.Ser99fs
NP_001341549.1:p.Ser242fs
NP_001341557.1:p.Ser340fs
NP_001341558.1:p.Ser307fs
NP_001341559.1:p.Ser340fs
LRG_216:g.32093del
NC_000003.11:g.37061933del
NM_000249.3:c.1017delC

Protein change:

S242fs

Links:

dbSNP: rs63750339

NCBI 1000 Genomes Browser:

rs63750339

Molecular consequence:

NM_001354621.2:c.-7del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-7del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-7del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.1017del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.723del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1017del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.723del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.1017del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.918del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.1017del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.-36-5195del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-36-5195del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-36-5195del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-36-5195del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106064	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000283994	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 15, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106064

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000283994

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 15, 2016)

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106064.2

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

Description

Coding sequence variation resulting in a stop codon

#	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 Invitae, SCV000283994.3

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

Description

This sequence change deletes 1 nucleotide from exon 11 of the MLH1 mRNA (c.1017delC), causing a frameshift at codon 340. This creates a premature translational stop signal (p.Ser340Profs*27) and is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been reported in an individual affected with colorectal cancer (PMID:16807412). This variant is also known as c.1017_1018delC in the literature. ClinVar contains an entry for this variant (Variation ID: 89606). For these reasons, this variant has been classified as 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: Nov 29, 2022

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