NM_000249.4(MLH1):c.85G>T (p.Ala29Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 5, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV000767178.17

Allele description [Variation Report for NM_000249.4(MLH1):c.85G>T (p.Ala29Ser)]

NM_000249.4(MLH1):c.85G>T (p.Ala29Ser)

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.85G>T (p.Ala29Ser)

HGVS:

NC_000003.12:g.36993632G>T
NG_007109.2:g.5283G>T
NG_008418.1:g.4673C>A
NM_000249.4:c.85G>TMANE SELECT
NM_001167617.3:c.-432G>T
NM_001167618.3:c.-861G>T
NM_001167619.3:c.-774G>T
NM_001258271.2:c.85G>T
NM_001258273.2:c.-548G>T
NM_001258274.3:c.-1011G>T
NM_001354615.2:c.-542G>T
NM_001354616.2:c.-542G>T
NM_001354617.2:c.-634G>T
NM_001354618.2:c.-866G>T
NM_001354619.2:c.-990G>T
NM_001354620.2:c.-200G>T
NM_001354621.2:c.-959G>T
NM_001354622.2:c.-1072G>T
NM_001354623.2:c.-981G>T
NM_001354624.2:c.-742G>T
NM_001354625.2:c.-640G>T
NM_001354626.2:c.-737G>T
NM_001354627.2:c.-969G>T
NM_001354628.2:c.85G>T
NM_001354629.2:c.85G>T
NM_001354630.2:c.85G>T
NP_000240.1:p.Ala29Ser
NP_000240.1:p.Ala29Ser
NP_001245200.1:p.Ala29Ser
NP_001341557.1:p.Ala29Ser
NP_001341558.1:p.Ala29Ser
NP_001341559.1:p.Ala29Ser
LRG_216t1:c.85G>T
LRG_216:g.5283G>T
LRG_216p1:p.Ala29Ser
NC_000003.11:g.37035123G>T
NM_000249.3:c.85G>T
NM_001167618.1:c.-861G>T
P40692:p.Ala29Ser
c.85G>T
p.A29S

Protein change:

A29S

Links:

UniProtKB: P40692#VAR_043386; dbSNP: rs63750656

NCBI 1000 Genomes Browser:

rs63750656

Molecular consequence:

NM_001167617.3:c.-432G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-861G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-774G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-548G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1011G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-542G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-542G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-634G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-866G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-990G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-200G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-959G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1072G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-981G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-742G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-640G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-737G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-969G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens ankyrin repeat domain 52, mRNA (cDNA clone IMAGE:5738580)
Homo sapiens ankyrin repeat domain 52, mRNA (cDNA clone IMAGE:5738580)
gi|27694352|gb|BC042070.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279067	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 3, 2020)	germline	clinical testing	Citation Link,
SCV002048891	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely benign (Nov 5, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279067

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 3, 2020)

germline

clinical testing

Citation Link,

SCV002048891

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely benign
(Nov 5, 2020)

germline

clinical testing

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

Details of each submission

From GeneDx, SCV000279067.9

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

Description

MLH1 c.-27C>A has been reported in cis with MLH1 c.85G>T (p.Ala29Ser) in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Raevaara 2005, Hitchins 2011, Ward 2013, Kwok 2014); Published functional studies, when MLH1 c.85G>T (p.Ala29Ser) is evaluated in isolation, demonstrate no damaging effect; however, the MLH1 c.[-27C>A;85G>T] haplotype results in constitutional MLH1 promoter methylation and reduced allelic expression (Raevaara 2005, Takahashi 2007, Hitchins 2011, Kwok 2014); While segregation data of MLH1 c.-27C>A alone is not available, the MLH1 c.[-27C>A;85G>T] haplotype segregates with disease in affected individuals from several unrelated families in published literature (Raevaara 2005, Hitchins 2011, Ward 2013, Kwok 2014); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24084575, 18383312, 12658575, 16083711, 17594722, 21120944, 22949387, 17370310, 17192056, 16995940, 22878509, 17510385, 21840485, 25345868, 27435373, 28152038, 29341452, 30283143)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048891.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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: Nov 3, 2024

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