NM_000249.4(MLH1):c.36C>G (p.Asp12Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 1, 2022
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:: RCV000130802.12

Allele description [Variation Report for NM_000249.4(MLH1):c.36C>G (p.Asp12Glu)]

NM_000249.4(MLH1):c.36C>G (p.Asp12Glu)

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.36C>G (p.Asp12Glu)

HGVS:

NC_000003.12:g.36993583C>G
NG_007109.2:g.5234C>G
NG_008418.1:g.4722G>C
NM_000249.4:c.36C>GMANE SELECT
NM_001167617.3:c.-481C>G
NM_001167618.3:c.-910C>G
NM_001167619.3:c.-823C>G
NM_001258271.2:c.36C>G
NM_001258273.2:c.-597C>G
NM_001258274.3:c.-1060C>G
NM_001354615.2:c.-591C>G
NM_001354616.2:c.-591C>G
NM_001354617.2:c.-683C>G
NM_001354618.2:c.-915C>G
NM_001354619.2:c.-1039C>G
NM_001354620.2:c.-249C>G
NM_001354621.2:c.-1008C>G
NM_001354622.2:c.-1121C>G
NM_001354623.2:c.-1030C>G
NM_001354624.2:c.-791C>G
NM_001354625.2:c.-689C>G
NM_001354626.2:c.-786C>G
NM_001354627.2:c.-1018C>G
NM_001354628.2:c.36C>G
NM_001354629.2:c.36C>G
NM_001354630.2:c.36C>G
NP_000240.1:p.Asp12Glu
NP_000240.1:p.Asp12Glu
NP_001245200.1:p.Asp12Glu
NP_001341557.1:p.Asp12Glu
NP_001341558.1:p.Asp12Glu
NP_001341559.1:p.Asp12Glu
LRG_216t1:c.36C>G
LRG_216:g.5234C>G
LRG_216p1:p.Asp12Glu
NC_000003.11:g.37035074C>G
NM_000249.3:c.36C>G
p.D12E

Protein change:

D12E

Links:

dbSNP: rs587782181

NCBI 1000 Genomes Browser:

rs587782181

Molecular consequence:

NM_001167617.3:c.-481C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-910C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-823C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-597C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1060C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-591C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-591C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-683C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-915C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1039C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-249C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1008C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1121C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1030C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-791C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-689C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-786C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1018C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.36C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.36C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.36C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.36C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.36C>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
SCV000185698	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 14, 2019)	germline	clinical testing	Citation Link,
SCV000689881	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2022)	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

SCV000185698

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 14, 2019)

germline

clinical testing

Citation Link,

SCV000689881

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 1, 2022)

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	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 Ambry Genetics, SCV000185698.8

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

Description

The p.D12E variant (also known as c.36C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 36. The aspartic acid at codon 12 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by BayesDel in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analysis (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of this variant 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

From Color Diagnostics, LLC DBA Color Health, SCV000689881.5

#	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 aspartic acid with glutamic acid at codon 12 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 hereditary cancer in the literature. This variant has been identified in 1/251418 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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