NM_000249.4(MLH1):c.2180A>G (p.His727Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 5, 2019
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:: RCV001227358.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2180A>G (p.His727Arg)]

NM_000249.4(MLH1):c.2180A>G (p.His727Arg)

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.2180A>G (p.His727Arg)

HGVS:

NC_000003.12:g.37050562A>G
NG_007109.2:g.62213A>G
NM_000249.4:c.2180A>GMANE SELECT
NM_001167617.3:c.1886A>G
NM_001167618.3:c.1457A>G
NM_001167619.3:c.1457A>G
NM_001258271.2:c.1973A>G
NM_001258273.2:c.1457A>G
NM_001258274.3:c.1457A>G
NM_001354615.2:c.1457A>G
NM_001354616.2:c.1457A>G
NM_001354617.2:c.1457A>G
NM_001354618.2:c.1457A>G
NM_001354619.2:c.1457A>G
NM_001354620.2:c.1886A>G
NM_001354621.2:c.1157A>G
NM_001354622.2:c.1157A>G
NM_001354623.2:c.1157A>G
NM_001354624.2:c.1106A>G
NM_001354625.2:c.1106A>G
NM_001354626.2:c.1106A>G
NM_001354627.2:c.1106A>G
NM_001354628.2:c.2087A>G
NM_001354629.2:c.2081A>G
NM_001354630.2:c.2015A>G
NP_000240.1:p.His727Arg
NP_001161089.1:p.His629Arg
NP_001161090.1:p.His486Arg
NP_001161091.1:p.His486Arg
NP_001245200.1:p.His658Arg
NP_001245202.1:p.His486Arg
NP_001245203.1:p.His486Arg
NP_001341544.1:p.His486Arg
NP_001341545.1:p.His486Arg
NP_001341546.1:p.His486Arg
NP_001341547.1:p.His486Arg
NP_001341548.1:p.His486Arg
NP_001341549.1:p.His629Arg
NP_001341550.1:p.His386Arg
NP_001341551.1:p.His386Arg
NP_001341552.1:p.His386Arg
NP_001341553.1:p.His369Arg
NP_001341554.1:p.His369Arg
NP_001341555.1:p.His369Arg
NP_001341556.1:p.His369Arg
NP_001341557.1:p.His696Arg
NP_001341558.1:p.His694Arg
NP_001341559.1:p.His672Arg
LRG_216t1:c.2180A>G
LRG_216:g.62213A>G
NC_000003.11:g.37092053A>G
NM_000249.3:c.2180A>G

Protein change:

H369R

Links:

dbSNP: rs104895002

NCBI 1000 Genomes Browser:

rs104895002

Molecular consequence:

NM_000249.4:c.2180A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1886A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1973A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1457A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1886A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1157A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1157A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1157A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1106A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1106A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1106A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1106A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2087A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2081A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2015A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

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nuclear RNA polymerase II second-largest subunit, partial [Eremalche exilis]
nuclear RNA polymerase II second-largest subunit, partial [Eremalche exilis]
gi|381354495|gb|AFG25966.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001399711	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 5, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001399711

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 5, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV001399711.4

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 727 of the MLH1 protein (p.His727Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine.

#	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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