NM_000249.4(MLH1):c.546-5del AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001705513.5

Allele description [Variation Report for NM_000249.4(MLH1):c.546-5del]

NM_000249.4(MLH1):c.546-5del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.546-5del

HGVS:

NC_000003.12:g.37011815del
NG_007109.2:g.23466del
NM_000249.4:c.546-5delMANE SELECT
NM_001167617.3:c.252-5del
NM_001167618.3:c.-178-5del
NM_001167619.3:c.-178-5del
NM_001258271.2:c.546-5del
NM_001258273.2:c.-178-5del
NM_001258274.3:c.-178-5del
NM_001354615.2:c.-178-5del
NM_001354616.2:c.-178-5del
NM_001354617.2:c.-178-5del
NM_001354618.2:c.-178-5del
NM_001354619.2:c.-178-5del
NM_001354620.2:c.252-5del
NM_001354621.2:c.-271-5del
NM_001354622.2:c.-384-5del
NM_001354623.2:c.-384-5del
NM_001354624.2:c.-281-5del
NM_001354625.2:c.-281-5del
NM_001354626.2:c.-281-5del
NM_001354627.2:c.-281-5del
NM_001354628.2:c.546-5del
NM_001354629.2:c.447-5del
NM_001354630.2:c.546-5del
LRG_216t1:c.546-5del
LRG_216:g.23466del
NC_000003.11:g.37053303del
NC_000003.11:g.37053306del
NM_000249.3:c.546-5del
NM_000249.3:c.546-5del
NM_000249.3:c.546-5delT

Links:

dbSNP: rs1553643965

NCBI 1000 Genomes Browser:

rs1553643965

Molecular consequence:

NM_000249.4:c.546-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.252-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.546-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.-178-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.252-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.-271-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.-384-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-384-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.-281-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-281-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-281-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-281-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.546-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.447-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.546-5del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000571207	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Nov 10, 2022)	germline	clinical testing	Citation Link,
SCV004220891	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 21, 2023)	unknown	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

SCV000571207

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Nov 10, 2022)

germline

clinical testing

Citation Link,

SCV004220891

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Sep 21, 2023)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000571207.6

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

Description

See Variant Classification Assertion Criteria.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220891.1

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

Description

To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251150 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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