NM_000249.4(MLH1):c.181A>G (p.Ile61Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 9, 2022
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:: RCV001013300.9

Allele description [Variation Report for NM_000249.4(MLH1):c.181A>G (p.Ile61Val)]

NM_000249.4(MLH1):c.181A>G (p.Ile61Val)

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.181A>G (p.Ile61Val)

HGVS:

NC_000003.12:g.36996683A>G
NG_007109.2:g.8334A>G
NG_008418.1:g.1622T>C
NM_000249.4:c.181A>GMANE SELECT
NM_001167617.3:c.-109A>G
NM_001167618.3:c.-543A>G
NM_001167619.3:c.-451A>G
NM_001258271.2:c.181A>G
NM_001258273.2:c.-517+3020A>G
NM_001258274.3:c.-688A>G
NM_001354615.2:c.-446A>G
NM_001354616.2:c.-451A>G
NM_001354617.2:c.-543A>G
NM_001354618.2:c.-543A>G
NM_001354619.2:c.-543A>G
NM_001354620.2:c.-109A>G
NM_001354621.2:c.-636A>G
NM_001354622.2:c.-749A>G
NM_001354623.2:c.-723+2793A>G
NM_001354624.2:c.-646A>G
NM_001354625.2:c.-549A>G
NM_001354626.2:c.-646A>G
NM_001354627.2:c.-646A>G
NM_001354628.2:c.181A>G
NM_001354629.2:c.181A>G
NM_001354630.2:c.181A>G
NP_000240.1:p.Ile61Val
NP_000240.1:p.Ile61Val
NP_001245200.1:p.Ile61Val
NP_001341557.1:p.Ile61Val
NP_001341558.1:p.Ile61Val
NP_001341559.1:p.Ile61Val
LRG_216t1:c.181A>G
LRG_216:g.8334A>G
LRG_216p1:p.Ile61Val
NC_000003.11:g.37038174A>G
NM_000249.3:c.181A>G

Protein change:

I61V

Links:

dbSNP: rs1060500690

NCBI 1000 Genomes Browser:

rs1060500690

Molecular consequence:

NM_001167617.3:c.-109A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-543A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-451A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-688A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-446A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-451A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-543A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-543A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-543A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-109A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-749A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-646A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-549A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-646A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-646A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3020A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2793A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.181A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.181A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.181A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.181A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.181A>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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PREDICTED: Brassica napus NAC domain-containing protein 6 (LOC111204246), mRNA
PREDICTED: Brassica napus NAC domain-containing protein 6 (LOC111204246), mRNA
gi|2258270806|ref|XM_022698533.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001173870	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 27, 2022)	germline	clinical testing	Citation Link,
SCV001358165	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528680	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (May 11, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001173870

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 27, 2022)

germline

clinical testing

Citation Link,

SCV001358165

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 9, 2022)

germline

clinical testing

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

SCV002528680

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(May 11, 2021)

germline

curation

Citation Link

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, curation

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 Ambry Genetics, SCV001173870.4

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

Description

The p.I61V variant (also known as c.181A>G), located in coding exon 2 of the MLH1 gene, results from an A to G substitution at nucleotide position 181. The isoleucine at codon 61 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001358165.3

#	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 valine at codon 61 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). 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 Sema4, Sema4, SCV002528680.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	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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