NM_000249.4(MLH1):c.1569G>T (p.Glu523Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 2, 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:: RCV000552506.6

Allele description [Variation Report for NM_000249.4(MLH1):c.1569G>T (p.Glu523Asp)]

NM_000249.4(MLH1):c.1569G>T (p.Glu523Asp)

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.1569G>T (p.Glu523Asp)

HGVS:

NC_000003.12:g.37040196G>T
NG_007109.2:g.51847G>T
NM_000249.4:c.1569G>TMANE SELECT
NM_001167617.3:c.1275G>T
NM_001167618.3:c.846G>T
NM_001167619.3:c.846G>T
NM_001258271.2:c.1569G>T
NM_001258273.2:c.846G>T
NM_001258274.3:c.846G>T
NM_001354615.2:c.846G>T
NM_001354616.2:c.846G>T
NM_001354617.2:c.846G>T
NM_001354618.2:c.846G>T
NM_001354619.2:c.846G>T
NM_001354620.2:c.1275G>T
NM_001354621.2:c.546G>T
NM_001354622.2:c.546G>T
NM_001354623.2:c.546G>T
NM_001354624.2:c.495G>T
NM_001354625.2:c.495G>T
NM_001354626.2:c.495G>T
NM_001354627.2:c.495G>T
NM_001354628.2:c.1569G>T
NM_001354629.2:c.1470G>T
NM_001354630.2:c.1569G>T
NP_000240.1:p.Glu523Asp
NP_000240.1:p.Glu523Asp
NP_001161089.1:p.Glu425Asp
NP_001161090.1:p.Glu282Asp
NP_001161091.1:p.Glu282Asp
NP_001245200.1:p.Glu523Asp
NP_001245202.1:p.Glu282Asp
NP_001245203.1:p.Glu282Asp
NP_001341544.1:p.Glu282Asp
NP_001341545.1:p.Glu282Asp
NP_001341546.1:p.Glu282Asp
NP_001341547.1:p.Glu282Asp
NP_001341548.1:p.Glu282Asp
NP_001341549.1:p.Glu425Asp
NP_001341550.1:p.Glu182Asp
NP_001341551.1:p.Glu182Asp
NP_001341552.1:p.Glu182Asp
NP_001341553.1:p.Glu165Asp
NP_001341554.1:p.Glu165Asp
NP_001341555.1:p.Glu165Asp
NP_001341556.1:p.Glu165Asp
NP_001341557.1:p.Glu523Asp
NP_001341558.1:p.Glu490Asp
NP_001341559.1:p.Glu523Asp
LRG_216t1:c.1569G>T
LRG_216:g.51847G>T
LRG_216p1:p.Glu523Asp
NC_000003.11:g.37081687G>T
NM_000249.3:c.1569G>T

Protein change:

E165D

Links:

dbSNP: rs63751680

NCBI 1000 Genomes Browser:

rs63751680

Molecular consequence:

NM_000249.4:c.1569G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1275G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1569G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.846G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1275G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.546G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.546G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.546G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.495G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.495G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.495G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.495G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1569G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1470G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1569G>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
SCV000625081	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 2, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28449805, 17510385, 30998989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625081

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 2, 2024)

germline

clinical testing

PubMed (4)
[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

Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome.

Sunga AY, Ricker C, Espenschied CR, Castillo D, Melas M, Herzog J, Bannon S, Cruz-Correa M, Lynch P, Solomon I, Gruber SB, Weitzel JN.

Cancer Genet. 2017 Apr;212-213:1-7. doi: 10.1016/j.cancergen.2017.01.003. Epub 2017 Feb 9.

PubMed [citation]

PMID:: 28449805
PMCID:: PMC8800930

Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C.

Cancer Res. 2007 May 15;67(10):4595-604.

PubMed [citation]

PMID:: 17510385

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000625081.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 523 of the MLH1 protein (p.Glu523Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 28449805). ClinVar contains an entry for this variant (Variation ID: 89792). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 17510385, 30998989). 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: Feb 28, 2024

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