NM_000249.4(MLH1):c.383C>G (p.Ala128Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 18, 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:: RCV000685803.6

Allele description [Variation Report for NM_000249.4(MLH1):c.383C>G (p.Ala128Gly)]

NM_000249.4(MLH1):c.383C>G (p.Ala128Gly)

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.383C>G (p.Ala128Gly)

HGVS:

NC_000003.12:g.37006993C>G
NG_007109.2:g.18644C>G
NM_000249.4:c.383C>GMANE SELECT
NM_001167617.3:c.89C>G
NM_001167618.3:c.-341C>G
NM_001167619.3:c.-249C>G
NM_001258271.2:c.383C>G
NM_001258273.2:c.-341C>G
NM_001258274.3:c.-341C>G
NM_001354615.2:c.-249C>G
NM_001354616.2:c.-249C>G
NM_001354617.2:c.-341C>G
NM_001354618.2:c.-341C>G
NM_001354619.2:c.-341C>G
NM_001354620.2:c.89C>G
NM_001354621.2:c.-434C>G
NM_001354622.2:c.-547C>G
NM_001354623.2:c.-547C>G
NM_001354624.2:c.-444C>G
NM_001354625.2:c.-352C>G
NM_001354626.2:c.-444C>G
NM_001354627.2:c.-444C>G
NM_001354628.2:c.383C>G
NM_001354629.2:c.284C>G
NM_001354630.2:c.383C>G
NP_000240.1:p.Ala128Gly
NP_000240.1:p.Ala128Gly
NP_001161089.1:p.Ala30Gly
NP_001245200.1:p.Ala128Gly
NP_001341549.1:p.Ala30Gly
NP_001341557.1:p.Ala128Gly
NP_001341558.1:p.Ala95Gly
NP_001341559.1:p.Ala128Gly
LRG_216t1:c.383C>G
LRG_216:g.18644C>G
LRG_216p1:p.Ala128Gly
NC_000003.11:g.37048484C>G
NM_000249.3:c.383C>G

Protein change:

A128G

Links:

dbSNP: rs1064796093

NCBI 1000 Genomes Browser:

rs1064796093

Molecular consequence:

NM_001167618.3:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-249C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-249C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-249C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-341C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-434C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-547C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-547C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-444C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-352C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-444C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-444C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.383C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.89C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.383C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.89C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.383C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.284C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.383C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Homologene neighbors for GEO Profiles (Select 125841239) (0)
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Chromosome neighbors for GEO Profiles (Select 125841049) (18)
GEO Profiles
BATF basic leucine zipper ATF-like transcription factor [Homo sapiens]
BATF basic leucine zipper ATF-like transcription factor [Homo sapiens]
Gene ID:10538

Gene
Gene Links for GEO Profiles (Select 125833713) (1)
Gene
ALDOB aldolase, fructose-bisphosphate B [Homo sapiens]
ALDOB aldolase, fructose-bisphosphate B [Homo sapiens]
Gene ID:229

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000813301	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9218993, 12810663, 17135187, 17510385, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813301

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 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

Mean age of tumor onset in hereditary nonpolyposis colorectal cancer (HNPCC) families correlates with the presence of mutations in DNA mismatch repair genes.

Pensotti V, Radice P, Presciuttini S, Calistri D, Gazzoli I, Grimalt Perez A, Mondini P, Buonsanti G, Sala P, Rossetti C, Ranzani GN, Bertario L, Pierotti MA.

Genes Chromosomes Cancer. 1997 Jul;19(3):135-42.

PubMed [citation]

PMID:: 9218993

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]

PMID:: 12810663

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000813301.5

#	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 glycine, which is neutral and non-polar, at codon 128 of the MLH1 protein (p.Ala128Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 422919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Ala128 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9218993, 12810663, 17135187, 17510385, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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