NM_000249.4(MLH1):c.22del (p.Ile8fs) AND Lynch syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 14, 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:: RCV004006849.2

Allele description [Variation Report for NM_000249.4(MLH1):c.22del (p.Ile8fs)]

NM_000249.4(MLH1):c.22del (p.Ile8fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.22del (p.Ile8fs)

HGVS:

NC_000003.12:g.36993569del
NG_007109.2:g.5220del
NG_008418.1:g.4736del
NM_000249.4:c.22delMANE SELECT
NM_001167617.3:c.-495del
NM_001167618.3:c.-924del
NM_001167619.3:c.-837del
NM_001258271.2:c.22del
NM_001258273.2:c.-611del
NM_001258274.3:c.-1074del
NM_001354615.2:c.-605del
NM_001354616.2:c.-605del
NM_001354617.2:c.-697del
NM_001354618.2:c.-929del
NM_001354619.2:c.-1053del
NM_001354620.2:c.-263del
NM_001354621.2:c.-1022del
NM_001354622.2:c.-1135del
NM_001354623.2:c.-1044del
NM_001354624.2:c.-805del
NM_001354625.2:c.-703del
NM_001354626.2:c.-800del
NM_001354627.2:c.-1032del
NM_001354628.2:c.22del
NM_001354629.2:c.22del
NM_001354630.2:c.22del
NP_000240.1:p.Ile8fs
NP_001245200.1:p.Ile8fs
NP_001341557.1:p.Ile8fs
NP_001341558.1:p.Ile8fs
NP_001341559.1:p.Ile8fs
LRG_216:g.5220del
NC_000003.11:g.37035060del

Protein change:

I8fs

Links:

dbSNP: rs2125693612

NCBI 1000 Genomes Browser:

rs2125693612

Molecular consequence:

NM_001167617.3:c.-495del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-924del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-837del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-611del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1074del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-605del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-605del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-697del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-929del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1053del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-263del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1022del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1135del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1044del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-805del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-703del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-800del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1032del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

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AAB39333 (0)
PopSet
Mycobacterium sp. UM_Kg27 contig000106, whole genome shotgun sequence
Mycobacterium sp. UM_Kg27 contig000106, whole genome shotgun sequence
gi|807963071|gb|JRMM01000106.1||gnl JRMM01|contig000106

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004843562	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2023)	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

SCV004843562

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 14, 2023)

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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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 All of Us Research Program, National Institutes of Health, SCV004843562.1

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

Description

This variant deletes 1 nucleotide in exon 1/19 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. To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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