NM_000249.4(MLH1):c.96C>G (p.Ile32Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000581627.7

Allele description [Variation Report for NM_000249.4(MLH1):c.96C>G (p.Ile32Met)]

NM_000249.4(MLH1):c.96C>G (p.Ile32Met)

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.96C>G (p.Ile32Met)

HGVS:

NC_000003.12:g.36993643C>G
NG_007109.2:g.5294C>G
NG_008418.1:g.4662G>C
NM_000249.4:c.96C>GMANE SELECT
NM_001167617.3:c.-421C>G
NM_001167618.3:c.-850C>G
NM_001167619.3:c.-763C>G
NM_001258271.2:c.96C>G
NM_001258273.2:c.-537C>G
NM_001258274.3:c.-1000C>G
NM_001354615.2:c.-531C>G
NM_001354616.2:c.-531C>G
NM_001354617.2:c.-623C>G
NM_001354618.2:c.-855C>G
NM_001354619.2:c.-979C>G
NM_001354620.2:c.-189C>G
NM_001354621.2:c.-948C>G
NM_001354622.2:c.-1061C>G
NM_001354623.2:c.-970C>G
NM_001354624.2:c.-731C>G
NM_001354625.2:c.-629C>G
NM_001354626.2:c.-726C>G
NM_001354627.2:c.-958C>G
NM_001354628.2:c.96C>G
NM_001354629.2:c.96C>G
NM_001354630.2:c.96C>G
NP_000240.1:p.Ile32Met
NP_000240.1:p.Ile32Met
NP_001245200.1:p.Ile32Met
NP_001341557.1:p.Ile32Met
NP_001341558.1:p.Ile32Met
NP_001341559.1:p.Ile32Met
LRG_216t1:c.96C>G
LRG_216:g.5294C>G
LRG_216p1:p.Ile32Met
NC_000003.11:g.37035134C>G
NM_000249.3:c.96C>G

Protein change:

I32M

Links:

dbSNP: rs1553637356

NCBI 1000 Genomes Browser:

rs1553637356

Molecular consequence:

NM_001167617.3:c.-421C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-850C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-763C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-537C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1000C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-531C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-531C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-623C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-855C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-979C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-189C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-948C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1061C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-970C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-731C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-629C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-726C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-958C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.96C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.96C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.96C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.96C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.96C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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cytochrome b (mitochondrion) [Drosophila melanogaster]
cytochrome b (mitochondrion) [Drosophila melanogaster]
gi|667699640|gnl|REF_FlyBase|CG3409 ref|YP_009047277.1|

Protein
NADH dehydrogenase subunit 4 (mitochondrion) [Phaner electromontis]
NADH dehydrogenase subunit 4 (mitochondrion) [Phaner electromontis]
gi|712042457|gb|AIW64424.1|

Protein
probable E3 ubiquitin-protein ligase MARCHF10 isoform 1 [Homo sapiens]
probable E3 ubiquitin-protein ligase MARCHF10 isoform 1 [Homo sapiens]
gi|154937340|ref|NP_689811.2|

Protein
LOC117397241 [Acipenser ruthenus]
LOC117397241 [Acipenser ruthenus]
Gene ID:117397241

Gene
LOC117396675 [Acipenser ruthenus]
LOC117396675 [Acipenser ruthenus]
Gene ID:117396675

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000689935	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000822027	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004006418	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000689935

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 27, 2023)

germline

clinical testing

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

SCV000822027

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2018)

germline

clinical testing

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

SCV004006418

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 12, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000689935.3

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

Description

This missense variant replaces isoleucine with methionine at codon 32 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.95T>A (p.Ile32Asn), has been described as disease-causing (ClinVar variation ID: 823364), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

From GeneKor MSA, SCV000822027.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV004006418.2

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

Description

The p.I32M variant (also known as c.96C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 96. The isoleucine at codon 32 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.

#	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 7, 2024

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