NM_000249.4(MLH1):c.2157T>G (p.Ile719Met) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 27, 2021
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:: RCV001361331.3

Allele description [Variation Report for NM_000249.4(MLH1):c.2157T>G (p.Ile719Met)]

NM_000249.4(MLH1):c.2157T>G (p.Ile719Met)

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.2157T>G (p.Ile719Met)

HGVS:

NC_000003.12:g.37050539T>G
NG_007109.2:g.62190T>G
NM_000249.4:c.2157T>GMANE SELECT
NM_001167617.3:c.1863T>G
NM_001167618.3:c.1434T>G
NM_001167619.3:c.1434T>G
NM_001258271.2:c.1950T>G
NM_001258273.2:c.1434T>G
NM_001258274.3:c.1434T>G
NM_001354615.2:c.1434T>G
NM_001354616.2:c.1434T>G
NM_001354617.2:c.1434T>G
NM_001354618.2:c.1434T>G
NM_001354619.2:c.1434T>G
NM_001354620.2:c.1863T>G
NM_001354621.2:c.1134T>G
NM_001354622.2:c.1134T>G
NM_001354623.2:c.1134T>G
NM_001354624.2:c.1083T>G
NM_001354625.2:c.1083T>G
NM_001354626.2:c.1083T>G
NM_001354627.2:c.1083T>G
NM_001354628.2:c.2064T>G
NM_001354629.2:c.2058T>G
NM_001354630.2:c.1992T>G
NP_000240.1:p.Ile719Met
NP_001161089.1:p.Ile621Met
NP_001161090.1:p.Ile478Met
NP_001161091.1:p.Ile478Met
NP_001245200.1:p.Ile650Met
NP_001245202.1:p.Ile478Met
NP_001245203.1:p.Ile478Met
NP_001341544.1:p.Ile478Met
NP_001341545.1:p.Ile478Met
NP_001341546.1:p.Ile478Met
NP_001341547.1:p.Ile478Met
NP_001341548.1:p.Ile478Met
NP_001341549.1:p.Ile621Met
NP_001341550.1:p.Ile378Met
NP_001341551.1:p.Ile378Met
NP_001341552.1:p.Ile378Met
NP_001341553.1:p.Ile361Met
NP_001341554.1:p.Ile361Met
NP_001341555.1:p.Ile361Met
NP_001341556.1:p.Ile361Met
NP_001341557.1:p.Ile688Met
NP_001341558.1:p.Ile686Met
NP_001341559.1:p.Ile664Met
LRG_216:g.62190T>G
NC_000003.11:g.37092030T>G

Protein change:

I361M

Links:

dbSNP: rs2148523430

NCBI 1000 Genomes Browser:

rs2148523430

Molecular consequence:

NM_000249.4:c.2157T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1863T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1950T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1863T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1134T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1134T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1134T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1083T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1083T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1083T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1083T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2064T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2058T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1992T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Homo sapiens cDNA clone IMAGE:4822215
Homo sapiens cDNA clone IMAGE:4822215
gi|27503483|gb|BC042457.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001557304	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 27, 2021)	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

SCV001557304

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 27, 2021)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, SCV001557304.2

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

Description

This sequence change replaces isoleucine with methionine at codon 719 of the MLH1 protein (p.Ile719Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. 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: "Benign"; Align-GVGD: "Class C0"). 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.

#	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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