NM_000249.4(MLH1):c.2198A>G (p.His733Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 23, 2023
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:: RCV001304503.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2198A>G (p.His733Arg)]

NM_000249.4(MLH1):c.2198A>G (p.His733Arg)

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.2198A>G (p.His733Arg)

HGVS:

NC_000003.12:g.37050580A>G
NG_007109.2:g.62231A>G
NM_000249.4:c.2198A>GMANE SELECT
NM_001167617.3:c.1904A>G
NM_001167618.3:c.1475A>G
NM_001167619.3:c.1475A>G
NM_001258271.2:c.1991A>G
NM_001258273.2:c.1475A>G
NM_001258274.3:c.1475A>G
NM_001354615.2:c.1475A>G
NM_001354616.2:c.1475A>G
NM_001354617.2:c.1475A>G
NM_001354618.2:c.1475A>G
NM_001354619.2:c.1475A>G
NM_001354620.2:c.1904A>G
NM_001354621.2:c.1175A>G
NM_001354622.2:c.1175A>G
NM_001354623.2:c.1175A>G
NM_001354624.2:c.1124A>G
NM_001354625.2:c.1124A>G
NM_001354626.2:c.1124A>G
NM_001354627.2:c.1124A>G
NM_001354628.2:c.2105A>G
NM_001354629.2:c.2099A>G
NM_001354630.2:c.2033A>G
NP_000240.1:p.His733Arg
NP_000240.1:p.His733Arg
NP_001161089.1:p.His635Arg
NP_001161090.1:p.His492Arg
NP_001161091.1:p.His492Arg
NP_001245200.1:p.His664Arg
NP_001245202.1:p.His492Arg
NP_001245203.1:p.His492Arg
NP_001341544.1:p.His492Arg
NP_001341545.1:p.His492Arg
NP_001341546.1:p.His492Arg
NP_001341547.1:p.His492Arg
NP_001341548.1:p.His492Arg
NP_001341549.1:p.His635Arg
NP_001341550.1:p.His392Arg
NP_001341551.1:p.His392Arg
NP_001341552.1:p.His392Arg
NP_001341553.1:p.His375Arg
NP_001341554.1:p.His375Arg
NP_001341555.1:p.His375Arg
NP_001341556.1:p.His375Arg
NP_001341557.1:p.His702Arg
NP_001341558.1:p.His700Arg
NP_001341559.1:p.His678Arg
LRG_216t1:c.2198A>G
LRG_216:g.62231A>G
LRG_216p1:p.His733Arg
NC_000003.11:g.37092071A>G
NM_000249.3:c.2198A>G

Protein change:

H375R

Links:

dbSNP: rs770579083

NCBI 1000 Genomes Browser:

rs770579083

Molecular consequence:

NM_000249.4:c.2198A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1991A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1175A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1175A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1175A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1124A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1124A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1124A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1124A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2105A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2099A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2033A>G - 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
SCV001493786	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 23, 2023)	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

SCV001493786

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 23, 2023)

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, SCV001493786.3

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

Description

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 733 of the MLH1 protein (p.His733Arg). This variant is present in population databases (rs770579083, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 479690). 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. 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: Sep 29, 2024

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