NM_000249.4(MLH1):c.2153A>C (p.His718Pro) AND Hereditary nonpolyposis colorectal neoplasms

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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 16, 2022
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:: RCV000694232.3

Allele description

NM_000249.4(MLH1):c.2153A>C (p.His718Pro)

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.2153A>C (p.His718Pro)

HGVS:

NC_000003.12:g.37050535A>C
NG_007109.2:g.62186A>C
NM_000249.4:c.2153A>CMANE SELECT
NM_001167617.3:c.1859A>C
NM_001167618.3:c.1430A>C
NM_001167619.3:c.1430A>C
NM_001258271.2:c.1946A>C
NM_001258273.2:c.1430A>C
NM_001258274.3:c.1430A>C
NM_001354615.2:c.1430A>C
NM_001354616.2:c.1430A>C
NM_001354617.2:c.1430A>C
NM_001354618.2:c.1430A>C
NM_001354619.2:c.1430A>C
NM_001354620.2:c.1859A>C
NM_001354621.2:c.1130A>C
NM_001354622.2:c.1130A>C
NM_001354623.2:c.1130A>C
NM_001354624.2:c.1079A>C
NM_001354625.2:c.1079A>C
NM_001354626.2:c.1079A>C
NM_001354627.2:c.1079A>C
NM_001354628.2:c.2060A>C
NM_001354629.2:c.2054A>C
NM_001354630.2:c.1988A>C
NP_000240.1:p.His718Pro
NP_000240.1:p.His718Pro
NP_001161089.1:p.His620Pro
NP_001161090.1:p.His477Pro
NP_001161091.1:p.His477Pro
NP_001245200.1:p.His649Pro
NP_001245202.1:p.His477Pro
NP_001245203.1:p.His477Pro
NP_001341544.1:p.His477Pro
NP_001341545.1:p.His477Pro
NP_001341546.1:p.His477Pro
NP_001341547.1:p.His477Pro
NP_001341548.1:p.His477Pro
NP_001341549.1:p.His620Pro
NP_001341550.1:p.His377Pro
NP_001341551.1:p.His377Pro
NP_001341552.1:p.His377Pro
NP_001341553.1:p.His360Pro
NP_001341554.1:p.His360Pro
NP_001341555.1:p.His360Pro
NP_001341556.1:p.His360Pro
NP_001341557.1:p.His687Pro
NP_001341558.1:p.His685Pro
NP_001341559.1:p.His663Pro
LRG_216t1:c.2153A>C
LRG_216:g.62186A>C
LRG_216p1:p.His718Pro
NC_000003.11:g.37092026A>C
NC_000003.11:g.37092026A>C
NM_000249.3:c.2153A>C

Protein change:

H360P

Links:

dbSNP: rs587778983

NCBI 1000 Genomes Browser:

rs587778983

Molecular consequence:

NM_000249.4:c.2153A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1859A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1946A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1430A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1859A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1130A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1130A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1130A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1079A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1079A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1079A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1079A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2060A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2054A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1988A>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
SCV000822667	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 16, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19324997, 21520333, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000822667

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 16, 2022)

germline

clinical testing

PubMed (3)
[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

Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas.

Pino MS, Mino-Kenudson M, Wildemore BM, Ganguly A, Batten J, Sperduti I, Iafrate AJ, Chung DC.

J Mol Diagn. 2009 May;11(3):238-47. doi: 10.2353/jmoldx.2009.080142. Epub 2009 Mar 26.

PubMed [citation]

PMID:: 19324997
PMCID:: PMC2671341

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000822667.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 90071). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 19324997, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 718 of the MLH1 protein (p.His718Pro).

#	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 14, 2024

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