NM_000249.4(MLH1):c.92C>G (p.Ala31Gly) AND Lynch syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000161932.4

Allele description [Variation Report for NM_000249.4(MLH1):c.92C>G (p.Ala31Gly)]

NM_000249.4(MLH1):c.92C>G (p.Ala31Gly)

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.92C>G (p.Ala31Gly)

HGVS:

NC_000003.12:g.36993639C>G
NG_007109.2:g.5290C>G
NG_008418.1:g.4666G>C
NM_000249.4:c.92C>GMANE SELECT
NM_001167617.3:c.-425C>G
NM_001167618.3:c.-854C>G
NM_001167619.3:c.-767C>G
NM_001258271.2:c.92C>G
NM_001258273.2:c.-541C>G
NM_001258274.3:c.-1004C>G
NM_001354615.2:c.-535C>G
NM_001354616.2:c.-535C>G
NM_001354617.2:c.-627C>G
NM_001354618.2:c.-859C>G
NM_001354619.2:c.-983C>G
NM_001354620.2:c.-193C>G
NM_001354621.2:c.-952C>G
NM_001354622.2:c.-1065C>G
NM_001354623.2:c.-974C>G
NM_001354624.2:c.-735C>G
NM_001354625.2:c.-633C>G
NM_001354626.2:c.-730C>G
NM_001354627.2:c.-962C>G
NM_001354628.2:c.92C>G
NM_001354629.2:c.92C>G
NM_001354630.2:c.92C>G
NP_000240.1:p.Ala31Gly
NP_000240.1:p.Ala31Gly
NP_001245200.1:p.Ala31Gly
NP_001341557.1:p.Ala31Gly
NP_001341558.1:p.Ala31Gly
NP_001341559.1:p.Ala31Gly
LRG_216t1:c.92C>G
LRG_216:g.5290C>G
LRG_216p1:p.Ala31Gly
NC_000003.11:g.37035130C>G
NM_000249.3:c.92C>G

Protein change:

A31G

Links:

dbSNP: rs730882127

NCBI 1000 Genomes Browser:

rs730882127

Molecular consequence:

NM_001167617.3:c.-425C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-854C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-767C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-541C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1004C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-535C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-535C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-627C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-859C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-983C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-193C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-952C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1065C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-974C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-735C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-633C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-730C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-962C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.92C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211916	Labcorp Genetics (formerly Invitae), Labcorp	no assertion criteria provided	Uncertain significance (Feb 18, 2015)	germline	clinical testing
SCV004835233	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211916

Labcorp Genetics (formerly Invitae), Labcorp

no assertion criteria provided

Uncertain significance
(Feb 18, 2015)

germline

clinical testing

SCV004835233

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	18	not provided	not provided	108544	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000211916.1

#	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

From All of Us Research Program, National Institutes of Health, SCV004835233.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces alanine with glycine at codon 31 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 been identified in 22/282508 chromosomes 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	108544	not provided	not provided		18	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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