NM_000249.4(MLH1):c.383C>G (p.Ala128Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 28, 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:: RCV001183213.7

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001348880	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002623568	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 20, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001348880

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 28, 2023)

germline

clinical testing

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

SCV002623568

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 20, 2023)

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	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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001348880.3

#	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 alanine with glycine at codon 128 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.382G>C (p.Ala128Pro), is considered to be disease-causing (ClinVar variation ID: 90199), 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 Ambry Genetics, SCV002623568.3

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

Description

The p.A128G variant (also known as c.383C>G), located in coding exon 5 of the MLH1 gene, results from a C to G substitution at nucleotide position 383. The alanine at codon 128 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Last Updated: Sep 29, 2024

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