NM_000249.4(MLH1):c.224T>C (p.Ile75Thr) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 6, 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:: RCV000547962.4

Allele description [Variation Report for NM_000249.4(MLH1):c.224T>C (p.Ile75Thr)]

NM_000249.4(MLH1):c.224T>C (p.Ile75Thr)

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.224T>C (p.Ile75Thr)

HGVS:

NC_000003.12:g.37000971T>C
NG_007109.2:g.12622T>C
NM_000249.4:c.224T>CMANE SELECT
NM_001167617.3:c.-66T>C
NM_001167618.3:c.-500T>C
NM_001167619.3:c.-408T>C
NM_001258271.2:c.224T>C
NM_001258273.2:c.-500T>C
NM_001258274.3:c.-500T>C
NM_001354615.2:c.-403T>C
NM_001354616.2:c.-408T>C
NM_001354617.2:c.-500T>C
NM_001354618.2:c.-500T>C
NM_001354619.2:c.-500T>C
NM_001354620.2:c.-66T>C
NM_001354621.2:c.-593T>C
NM_001354622.2:c.-706T>C
NM_001354623.2:c.-706T>C
NM_001354624.2:c.-603T>C
NM_001354625.2:c.-506T>C
NM_001354626.2:c.-603T>C
NM_001354627.2:c.-603T>C
NM_001354628.2:c.224T>C
NM_001354629.2:c.208-3430T>C
NM_001354630.2:c.224T>C
NP_000240.1:p.Ile75Thr
NP_000240.1:p.Ile75Thr
NP_001245200.1:p.Ile75Thr
NP_001341557.1:p.Ile75Thr
NP_001341559.1:p.Ile75Thr
LRG_216t1:c.224T>C
LRG_216:g.12622T>C
LRG_216p1:p.Ile75Thr
NC_000003.11:g.37042462T>C
NM_000249.3:c.224T>C

Protein change:

I75T

Links:

dbSNP: rs876660839

NCBI 1000 Genomes Browser:

rs876660839

Molecular consequence:

NM_001167617.3:c.-66T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-408T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-403T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-408T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-66T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-593T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-706T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-706T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-506T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3430T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.224T>C - 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
SCV000625137	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35449176, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625137

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 6, 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

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Hu L, Sun J, Li Z, Qu Z, Liu Y, Wan Q, Liu J, Ding X, Zang F, Zhang J, Yao L, Xu Y, Wang Y, Xie Y.

NPJ Breast Cancer. 2022 Apr 21;8(1):52. doi: 10.1038/s41523-022-00417-x.

PubMed [citation]

PMID:: 35449176
PMCID:: PMC9023502

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, SCV000625137.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 75 of the MLH1 protein (p.Ile75Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 234084). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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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