NM_000249.4(MLH1):c.195del (p.Thr66fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 13, 2023
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:: RCV003584541.1

Allele description [Variation Report for NM_000249.4(MLH1):c.195del (p.Thr66fs)]

NM_000249.4(MLH1):c.195del (p.Thr66fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.195del (p.Thr66fs)

HGVS:

NC_000003.12:g.36996697del
NG_007109.2:g.8348del
NG_008418.1:g.1608del
NM_000249.4:c.195delMANE SELECT
NM_001167617.3:c.-95del
NM_001167618.3:c.-529del
NM_001167619.3:c.-437del
NM_001258271.2:c.195del
NM_001258273.2:c.-517+3034del
NM_001258274.3:c.-674del
NM_001354615.2:c.-432del
NM_001354616.2:c.-437del
NM_001354617.2:c.-529del
NM_001354618.2:c.-529del
NM_001354619.2:c.-529del
NM_001354620.2:c.-95del
NM_001354621.2:c.-622del
NM_001354622.2:c.-735del
NM_001354623.2:c.-723+2807del
NM_001354624.2:c.-632del
NM_001354625.2:c.-535del
NM_001354626.2:c.-632del
NM_001354627.2:c.-632del
NM_001354628.2:c.195del
NM_001354629.2:c.195del
NM_001354630.2:c.195del
NP_000240.1:p.Thr66fs
NP_001245200.1:p.Thr66fs
NP_001341557.1:p.Thr66fs
NP_001341558.1:p.Thr66fs
NP_001341559.1:p.Thr66fs
LRG_216:g.8348del
NC_000003.11:g.37038188del

Protein change:

T66fs

Links:

dbSNP: rs267607715

NCBI 1000 Genomes Browser:

rs267607715

Molecular consequence:

NM_001167617.3:c.-95del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-529del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-437del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-674del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-432del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-437del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-529del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-529del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-529del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-95del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-622del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-735del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-632del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-535del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-632del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-632del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.195del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.195del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.195del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.195del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.195del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.-517+3034del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2807del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004359167	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18566915, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004359167

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 13, 2023)

germline

clinical testing

PubMed (2)
[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

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004359167.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant deletes 1 nucleotide in exon 2 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in a cohort of Danish Lynch syndrome families (PMID: 18566915). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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: May 7, 2024

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