NM_000249.4(MLH1):c.174G>T (p.Leu58Phe) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 10, 2019
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:: RCV001058414.5

Allele description [Variation Report for NM_000249.4(MLH1):c.174G>T (p.Leu58Phe)]

NM_000249.4(MLH1):c.174G>T (p.Leu58Phe)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.174G>T (p.Leu58Phe)

HGVS:

NC_000003.12:g.36996676G>T
NG_007109.2:g.8327G>T
NG_008418.1:g.1629C>A
NM_000249.4:c.174G>TMANE SELECT
NM_001167617.3:c.-116G>T
NM_001167618.3:c.-550G>T
NM_001167619.3:c.-458G>T
NM_001258271.2:c.174G>T
NM_001258273.2:c.-517+3013G>T
NM_001258274.3:c.-695G>T
NM_001354615.2:c.-453G>T
NM_001354616.2:c.-458G>T
NM_001354617.2:c.-550G>T
NM_001354618.2:c.-550G>T
NM_001354619.2:c.-550G>T
NM_001354620.2:c.-116G>T
NM_001354621.2:c.-643G>T
NM_001354622.2:c.-756G>T
NM_001354623.2:c.-723+2786G>T
NM_001354624.2:c.-653G>T
NM_001354625.2:c.-556G>T
NM_001354626.2:c.-653G>T
NM_001354627.2:c.-653G>T
NM_001354628.2:c.174G>T
NM_001354629.2:c.174G>T
NM_001354630.2:c.174G>T
NP_000240.1:p.Leu58Phe
NP_001245200.1:p.Leu58Phe
NP_001341557.1:p.Leu58Phe
NP_001341558.1:p.Leu58Phe
NP_001341559.1:p.Leu58Phe
LRG_216t1:c.174G>T
LRG_216:g.8327G>T
NC_000003.11:g.37038167G>T
NM_000249.3:c.174G>T

Protein change:

L58F

Links:

dbSNP: rs762162504

NCBI 1000 Genomes Browser:

rs762162504

Molecular consequence:

NM_001167617.3:c.-116G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-550G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-458G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-695G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-453G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-458G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-550G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-550G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-550G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-116G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-643G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-756G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-653G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-556G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-653G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-653G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3013G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2786G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001222980	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 10, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10612827, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001222980

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 10, 2019)

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

UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.

Béroud C, Collod-Béroud G, Boileau C, Soussi T, Junien C.

Hum Mutat. 2000;15(1):86-94.

PubMed [citation]

PMID:: 10612827

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001222980.4

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 58 of the MLH1 protein (p.Leu58Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

#	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

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