NM_000249.4(MLH1):c.694G>A (p.Gly232Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 4, 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:: RCV002527178.2

Allele description [Variation Report for NM_000249.4(MLH1):c.694G>A (p.Gly232Arg)]

NM_000249.4(MLH1):c.694G>A (p.Gly232Arg)

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.694G>A (p.Gly232Arg)

HGVS:

NC_000003.12:g.37014448G>A
NG_007109.2:g.26099G>A
NM_000249.4:c.694G>AMANE SELECT
NM_001167617.3:c.400G>A
NM_001167618.3:c.-30G>A
NM_001167619.3:c.-30G>A
NM_001258271.2:c.694G>A
NM_001258273.2:c.-30G>A
NM_001258274.3:c.-30G>A
NM_001354615.2:c.-30G>A
NM_001354616.2:c.-30G>A
NM_001354617.2:c.-30G>A
NM_001354618.2:c.-30G>A
NM_001354619.2:c.-30G>A
NM_001354620.2:c.400G>A
NM_001354621.2:c.-140+2349G>A
NM_001354622.2:c.-236G>A
NM_001354623.2:c.-236G>A
NM_001354624.2:c.-133G>A
NM_001354625.2:c.-133G>A
NM_001354626.2:c.-133G>A
NM_001354627.2:c.-133G>A
NM_001354628.2:c.694G>A
NM_001354629.2:c.595G>A
NM_001354630.2:c.694G>A
NP_000240.1:p.Gly232Arg
NP_000240.1:p.Gly232Arg
NP_001161089.1:p.Gly134Arg
NP_001245200.1:p.Gly232Arg
NP_001341549.1:p.Gly134Arg
NP_001341557.1:p.Gly232Arg
NP_001341558.1:p.Gly199Arg
NP_001341559.1:p.Gly232Arg
LRG_216t1:c.694G>A
LRG_216:g.26099G>A
LRG_216p1:p.Gly232Arg
NC_000003.11:g.37055939G>A
NM_000249.3:c.694G>A

Protein change:

G134R

Links:

dbSNP: rs1553645131

NCBI 1000 Genomes Browser:

rs1553645131

Molecular consequence:

NM_001167618.3:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-30G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-236G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-236G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-133G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-133G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-133G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-133G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-140+2349G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.694G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.400G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.694G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.400G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.694G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.694G>A - 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
SCV003225337	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21404117, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003225337

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2024)

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

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

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, SCV003225337.2

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 232 of the MLH1 protein (p.Gly232Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 21404117; Invitae). ClinVar contains an entry for this variant (Variation ID: 433854). 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%. Studies have shown that this missense change results in skipping of exon 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

#	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: May 1, 2024

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