NM_000249.4(MLH1):c.673dup (p.Ser225fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 9, 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:: RCV001862335.6

Allele description [Variation Report for NM_000249.4(MLH1):c.673dup (p.Ser225fs)]

NM_000249.4(MLH1):c.673dup (p.Ser225fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.673dup (p.Ser225fs)

HGVS:

NC_000003.12:g.37012095dup
NG_007109.2:g.23746dup
NM_000249.4:c.673dupMANE SELECT
NM_001167617.3:c.379dup
NM_001167618.3:c.-51dup
NM_001167619.3:c.-51dup
NM_001258271.2:c.673dup
NM_001258273.2:c.-51dup
NM_001258274.3:c.-51dup
NM_001354615.2:c.-51dup
NM_001354616.2:c.-51dup
NM_001354617.2:c.-51dup
NM_001354618.2:c.-51dup
NM_001354619.2:c.-51dup
NM_001354620.2:c.379dup
NM_001354621.2:c.-144dup
NM_001354622.2:c.-257dup
NM_001354623.2:c.-257dup
NM_001354624.2:c.-154dup
NM_001354625.2:c.-154dup
NM_001354626.2:c.-154dup
NM_001354627.2:c.-154dup
NM_001354628.2:c.673dup
NM_001354629.2:c.574dup
NM_001354630.2:c.673dup
NP_000240.1:p.Ser225fs
NP_001161089.1:p.Ser127fs
NP_001245200.1:p.Ser225fs
NP_001341549.1:p.Ser127fs
NP_001341557.1:p.Ser225fs
NP_001341558.1:p.Ser192fs
NP_001341559.1:p.Ser225fs
LRG_216t1:c.673dup
LRG_216:g.23746dup
NC_000003.11:g.37053585_37053586insA
NC_000003.11:g.37053586dup
NM_000249.3:c.673dupA
p.Ser225Lysfs*10

Protein change:

S127fs

Links:

dbSNP: rs1575469505

NCBI 1000 Genomes Browser:

rs1575469505

Molecular consequence:

NM_001167618.3:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-51dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-144dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-257dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-257dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-154dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-154dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-154dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-154dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.673dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.379dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.673dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.379dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.673dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.574dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.673dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

Clear Turn Off Turn On

UMC-p4mm3-001-e08 4mm ovarian follicle p4mm Sus scrofa cDNA 3', mRNA sequence
UMC-p4mm3-001-e08 4mm ovarian follicle p4mm Sus scrofa cDNA 3', mRNA sequence
gi|51311013|gnl|dbEST|25052406|gb|C 54.1|

Nucleotide
Rattus norvegicus coiled-coil domain containing 51 (Ccdc51), mRNA; nuclear gene ...
Rattus norvegicus coiled-coil domain containing 51 (Ccdc51), mRNA; nuclear gene for mitochondrial product
gi|2007537952|ref|NM_001014098.2|

Nucleotide
PREDICTED: Rattus norvegicus coiled-coil domain containing 51 (Ccdc51), transcri...
PREDICTED: Rattus norvegicus coiled-coil domain containing 51 (Ccdc51), transcript variant X1, mRNA
gi|2678965301|ref|XM_006243789.5|

Nucleotide
zinc finger E-box-binding homeobox 2 isoform 1 [Homo sapiens]
zinc finger E-box-binding homeobox 2 isoform 1 [Homo sapiens]
gi|7662184|ref|NP_055610.1|

Protein
JGI_CAAP6080.fwd NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7712506 5'...
JGI_CAAP6080.fwd NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7712506 5', mRNA sequence
gi|58783419|gnl|dbEST|27676811|gb|C 92.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002143439	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15713769, 24362816, 14635101, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002143439

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]

PMID:: 24362816
PMCID:: PMC4294709

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002143439.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ser225Lysfs*10) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 14635101). ClinVar contains an entry for this variant (Variation ID: 826590). 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: Sep 29, 2024

ClinVar

Relating variation to medicine