NM_000249.4(MLH1):c.1763T>C (p.Leu588Pro) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 31, 2015
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:: RCV001360319.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1763T>C (p.Leu588Pro)]

NM_000249.4(MLH1):c.1763T>C (p.Leu588Pro)

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.1763T>C (p.Leu588Pro)

HGVS:

NC_000003.12:g.37047550T>C
NG_007109.2:g.59201T>C
NM_000249.4:c.1763T>CMANE SELECT
NM_001167617.3:c.1469T>C
NM_001167618.3:c.1040T>C
NM_001167619.3:c.1040T>C
NM_001258271.2:c.1763T>C
NM_001258273.2:c.1040T>C
NM_001258274.3:c.1040T>C
NM_001354615.2:c.1040T>C
NM_001354616.2:c.1040T>C
NM_001354617.2:c.1040T>C
NM_001354618.2:c.1040T>C
NM_001354619.2:c.1040T>C
NM_001354620.2:c.1469T>C
NM_001354621.2:c.740T>C
NM_001354622.2:c.740T>C
NM_001354623.2:c.740T>C
NM_001354624.2:c.689T>C
NM_001354625.2:c.689T>C
NM_001354626.2:c.689T>C
NM_001354627.2:c.689T>C
NM_001354628.2:c.1763T>C
NM_001354629.2:c.1664T>C
NM_001354630.2:c.1732-967T>C
NP_000240.1:p.Leu588Pro
NP_000240.1:p.Leu588Pro
NP_001161089.1:p.Leu490Pro
NP_001161090.1:p.Leu347Pro
NP_001161091.1:p.Leu347Pro
NP_001245200.1:p.Leu588Pro
NP_001245202.1:p.Leu347Pro
NP_001245203.1:p.Leu347Pro
NP_001341544.1:p.Leu347Pro
NP_001341545.1:p.Leu347Pro
NP_001341546.1:p.Leu347Pro
NP_001341547.1:p.Leu347Pro
NP_001341548.1:p.Leu347Pro
NP_001341549.1:p.Leu490Pro
NP_001341550.1:p.Leu247Pro
NP_001341551.1:p.Leu247Pro
NP_001341552.1:p.Leu247Pro
NP_001341553.1:p.Leu230Pro
NP_001341554.1:p.Leu230Pro
NP_001341555.1:p.Leu230Pro
NP_001341556.1:p.Leu230Pro
NP_001341557.1:p.Leu588Pro
NP_001341558.1:p.Leu555Pro
LRG_216t1:c.1763T>C
LRG_216:g.59201T>C
LRG_216p1:p.Leu588Pro
NC_000003.11:g.37089041T>C
NM_000249.3:c.1763T>C
P40692:p.Leu588Pro

Protein change:

L230P

Links:

UniProtKB: P40692#VAR_012924; dbSNP: rs63750575

NCBI 1000 Genomes Browser:

rs63750575

Molecular consequence:

NM_001354630.2:c.1732-967T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1763T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1469T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1763T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1040T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1469T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.740T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.740T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.740T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.689T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.689T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.689T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.689T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1763T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1664T>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
SCV001556233	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 31, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10777691, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001556233

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 31, 2015)

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

Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds.

Nomura S, Sugano K, Kashiwabara H, Taniguchi T, Fukayama N, Fujita S, Akasu T, Moriya Y, Ohhigashi S, Kakizoe T, Sekiya T.

Biochem Biophys Res Commun. 2000 Apr 29;271(1):120-9.

PubMed [citation]

PMID:: 10777691

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 Invitae, SCV001556233.3

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

Description

An experimental study which evaluated the effect of this sequence change using a model organism system reported reductions in MMR activity and relative expression of the MSH1 protein (PMID:¬†17510385). This variant has been reported in the literature in an individual affected with hereditary nonpolyposis cancer (PMID: 10777691)¬†and is not present in population databases.¬†ClinVar contains an entry for this variant (RCV000075358). This sequence change replaces leucine with proline at codon 588 of the MLH1 protein (p.Leu588Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. In summary, this is a rare missense change that has been reported in an affected individual and has been shown to have some deleterious effect on protein function, which is suggestive of pathogenicity. However, evidence is insufficient at this time to prove that conclusively. 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 16, 2024

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