NM_000249.4(MLH1):c.292G>C (p.Gly98Arg) AND MLH1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 17, 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:: RCV003390769.4

Allele description [Variation Report for NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)]

NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)

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.292G>C (p.Gly98Arg)

HGVS:

NC_000003.12:g.37001039G>C
NG_007109.2:g.12690G>C
NM_000249.4:c.292G>CMANE SELECT
NM_001167617.3:c.3G>C
NM_001167618.3:c.-432G>C
NM_001167619.3:c.-340G>C
NM_001258271.2:c.292G>C
NM_001258273.2:c.-432G>C
NM_001258274.3:c.-432G>C
NM_001354615.2:c.-335G>C
NM_001354616.2:c.-340G>C
NM_001354617.2:c.-432G>C
NM_001354618.2:c.-432G>C
NM_001354619.2:c.-432G>C
NM_001354620.2:c.3G>C
NM_001354621.2:c.-525G>C
NM_001354622.2:c.-638G>C
NM_001354623.2:c.-638G>C
NM_001354624.2:c.-535G>C
NM_001354625.2:c.-438G>C
NM_001354626.2:c.-535G>C
NM_001354627.2:c.-535G>C
NM_001354628.2:c.292G>C
NM_001354629.2:c.208-3362G>C
NM_001354630.2:c.292G>C
NP_000240.1:p.Gly98Arg
NP_000240.1:p.Gly98Arg
NP_001161089.1:p.Met1Ile
NP_001245200.1:p.Gly98Arg
NP_001341549.1:p.Met1Ile
NP_001341557.1:p.Gly98Arg
NP_001341559.1:p.Gly98Arg
LRG_216t1:c.292G>C
LRG_216:g.12690G>C
LRG_216p1:p.Gly98Arg
NC_000003.11:g.37042530G>C
NM_000249.3:c.292G>C
NM_001167618.1:c.-432G>C

Protein change:

G98R

Links:

dbSNP: rs267607725

NCBI 1000 Genomes Browser:

rs267607725

Molecular consequence:

NM_001167618.3:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-340G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-340G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-432G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-525G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-638G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-638G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-438G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-535G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167617.3:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001354620.2:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001354629.2:c.208-3362G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: MLH1-related disorder
Synonyms:: MLH1-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004120073	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 17, 2022)	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

SCV004120073

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 17, 2022)

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004120073.1

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

Description

The MLH1 c.292G>C variant is predicted to result in the amino acid substitution p.Gly98Arg. In the primary transcript NM_000249.4, this variant is known as c.292G>C (p.Gly98Arg). The p.Gly98Arg variant has been reported in patients with hereditary nonpolyposis colorectal cancer (Patient 20 in Bujalkova et al. 2008. PubMed ID: 18772310; Case 2047/01 in Kovac et al. 2011. PubMed ID: 21671081). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37042530-G-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/90129). Of note, another variant impacting this same amino acid (p.Gly98Ser) has been documented; however, clinical or functional evidence was not provided (Ali et al. 2012. PubMed ID: 22290698). Although we suspect that the c.292G>C (p.Gly98Arg) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#	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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