NM_000249.4(MLH1):c.85G>T (p.Ala29Ser) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 31, 2023
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:: RCV000697498.15

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)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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testis-expressed protein 29 isoform 2 [Homo sapiens]
testis-expressed protein 29 isoform 2 [Homo sapiens]
gi|22748709|ref|NP_689537.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000826113	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 31, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 2408575, 22878509, 16083711, 17510385, 21840485, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826113

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 31, 2023)

germline

clinical testing

PubMed (6)
[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

[In vitro sensitivity test of anti-neoplastic agents and their enhancement by biscoclaurine alkaloid].

Sekiya S, Mogi M, Tanigawa S, Hayashi H, Uchiyama T, Okayasu M.

Gan To Kagaku Ryoho. 1985 Mar;12(3 Pt 1):524-9. Japanese.

PubMed [citation]

PMID:: 2408575

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

Ward RL, Dobbins T, Lindor NM, Rapkins RW, Hitchins MP.

Genet Med. 2013 Jan;15(1):25-35. doi: 10.1038/gim.2012.91. Epub 2012 Aug 9.

PubMed [citation]

PMID:: 22878509
PMCID:: PMC3908650

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826113.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 29 of the MLH1 protein (p.Ala29Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome, and in many individuals the variant has been reported on the same chromosome with the c.-27C>A promoter MLH1 variant. (PMID: 2408575, 16083711, 21840485, 22878509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90397). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 16083711, 17510385, 21840485). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

Last Updated: Nov 3, 2024

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