NM_000249.4(MLH1):c.1693A>T (p.Ile565Phe) AND Hereditary nonpolyposis colorectal neoplasms

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 3, 2024
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:: RCV000627705.7

Allele description

NM_000249.4(MLH1):c.1693A>T (p.Ile565Phe)

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.1693A>T (p.Ile565Phe)

Other names:

p.I565F:ATT>TTT

HGVS:

NC_000003.12:g.37042293A>T
NG_007109.2:g.53944A>T
NM_000249.4:c.1693A>TMANE SELECT
NM_001167617.3:c.1399A>T
NM_001167618.3:c.970A>T
NM_001167619.3:c.970A>T
NM_001258271.2:c.1693A>T
NM_001258273.2:c.970A>T
NM_001258274.3:c.970A>T
NM_001354615.2:c.970A>T
NM_001354616.2:c.970A>T
NM_001354617.2:c.970A>T
NM_001354618.2:c.970A>T
NM_001354619.2:c.970A>T
NM_001354620.2:c.1399A>T
NM_001354621.2:c.670A>T
NM_001354622.2:c.670A>T
NM_001354623.2:c.670A>T
NM_001354624.2:c.619A>T
NM_001354625.2:c.619A>T
NM_001354626.2:c.619A>T
NM_001354627.2:c.619A>T
NM_001354628.2:c.1693A>T
NM_001354629.2:c.1594A>T
NM_001354630.2:c.1693A>T
NP_000240.1:p.Ile565Phe
NP_000240.1:p.Ile565Phe
NP_001161089.1:p.Ile467Phe
NP_001161090.1:p.Ile324Phe
NP_001161091.1:p.Ile324Phe
NP_001245200.1:p.Ile565Phe
NP_001245202.1:p.Ile324Phe
NP_001245203.1:p.Ile324Phe
NP_001341544.1:p.Ile324Phe
NP_001341545.1:p.Ile324Phe
NP_001341546.1:p.Ile324Phe
NP_001341547.1:p.Ile324Phe
NP_001341548.1:p.Ile324Phe
NP_001341549.1:p.Ile467Phe
NP_001341550.1:p.Ile224Phe
NP_001341551.1:p.Ile224Phe
NP_001341552.1:p.Ile224Phe
NP_001341553.1:p.Ile207Phe
NP_001341554.1:p.Ile207Phe
NP_001341555.1:p.Ile207Phe
NP_001341556.1:p.Ile207Phe
NP_001341557.1:p.Ile565Phe
NP_001341558.1:p.Ile532Phe
NP_001341559.1:p.Ile565Phe
LRG_216t1:c.1693A>T
LRG_216:g.53944A>T
LRG_216p1:p.Ile565Phe
NC_000003.11:g.37083784A>T
NM_000249.3:c.1693A>T
P40692:p.Ile565Phe

Protein change:

I207F

Links:

UniProtKB: P40692#VAR_012923; dbSNP: rs63750062

NCBI 1000 Genomes Browser:

rs63750062

Molecular consequence:

NM_000249.4:c.1693A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1399A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1693A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.970A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1399A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.670A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.670A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.670A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.619A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.619A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.619A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.619A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1693A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1594A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1693A>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
SCV000543656	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 3, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9833759, 21404117, 21901500, 17510385, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543656

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 3, 2024)

germline

clinical testing

PubMed (5)
[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

Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.

Hutter P, Couturier A, Membrez V, Joris F, Sappino AP, Chappuis PO.

Int J Cancer. 1998 Dec 9;78(6):680-4.

PubMed [citation]

PMID:: 9833759

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000543656.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 565 of the MLH1 protein (p.Ile565Phe). This variant is present in population databases (rs63750062, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome. However, in one of these individuals a pathogenic allele was also identified in MSH2, which suggests that this c.1693A>T variant was not the primary cause of disease. (PMID: 9833759, 21404117, 21901500). ClinVar contains an entry for this variant (Variation ID: 89842). 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385). 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: Aug 4, 2024

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