NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 16, 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:: RCV000855650.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser)]

NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Inversion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser)

HGVS:

NC_000003.12:g.37048994_37048995inv
NG_007109.2:g.60645_60646inv
NM_000249.4:c.2080_2081invMANE SELECT
NM_001167617.3:c.1786_1787inv
NM_001167618.3:c.1357_1358inv
NM_001167619.3:c.1357_1358inv
NM_001258271.2:c.1896+1311_1896+1312inv
NM_001258273.2:c.1357_1358inv
NM_001258274.3:c.1357_1358inv
NM_001354615.2:c.1357_1358inv
NM_001354616.2:c.1357_1358inv
NM_001354617.2:c.1357_1358inv
NM_001354618.2:c.1357_1358inv
NM_001354619.2:c.1357_1358inv
NM_001354620.2:c.1786_1787inv
NM_001354621.2:c.1057_1058inv
NM_001354622.2:c.1057_1058inv
NM_001354623.2:c.1057_1058inv
NM_001354624.2:c.1006_1007inv
NM_001354625.2:c.1006_1007inv
NM_001354626.2:c.1006_1007inv
NM_001354627.2:c.1006_1007inv
NM_001354628.2:c.1987_1988inv
NM_001354629.2:c.1981_1982inv
NM_001354630.2:c.1915_1916inv
NP_000240.1:p.Glu694Ser
NP_001161089.1:p.Glu596Ser
NP_001161090.1:p.Glu453Ser
NP_001161091.1:p.Glu453Ser
NP_001245202.1:p.Glu453Ser
NP_001245203.1:p.Glu453Ser
NP_001341544.1:p.Glu453Ser
NP_001341545.1:p.Glu453Ser
NP_001341546.1:p.Glu453Ser
NP_001341547.1:p.Glu453Ser
NP_001341548.1:p.Glu453Ser
NP_001341549.1:p.Glu596Ser
NP_001341550.1:p.Glu353Ser
NP_001341551.1:p.Glu353Ser
NP_001341552.1:p.Glu353Ser
NP_001341553.1:p.Glu336Ser
NP_001341554.1:p.Glu336Ser
NP_001341555.1:p.Glu336Ser
NP_001341556.1:p.Glu336Ser
NP_001341557.1:p.Glu663Ser
NP_001341558.1:p.Glu661Ser
NP_001341559.1:p.Glu639Ser
LRG_216:g.60645_60646inv
NC_000003.11:g.37090485_37090486delinsTC
NC_000003.11:g.37090485_37090486inv
NM_000249.4:c.2080_2081delinsTCMANE SELECT

Protein change:

E336S

Links:

Molecular consequence:

NM_001258271.2:c.1896+1311_1896+1312inv - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2080_2081inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1786_1787inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1357_1358inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1786_1787inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1057_1058inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1057_1058inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1057_1058inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1006_1007inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1006_1007inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1006_1007inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1006_1007inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1987_1988inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1981_1982inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1915_1916inv - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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MGT9 magnesium transporter 9 [Arabidopsis thaliana]
MGT9 magnesium transporter 9 [Arabidopsis thaliana]
Gene ID:836577

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696143	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696143

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 16, 2023)

germline

clinical testing

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

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

The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance.

Varga E, Chao EC, Yeager ND.

Fam Cancer. 2015 Sep;14(3):481-5. doi: 10.1007/s10689-015-9790-3.

PubMed [citation]

PMID:: 25712765
PMCID:: PMC4559104

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696143.3

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

Description

Variant summary: MLH1 c.2080_2081delinsTC (p.Glu694Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This variant is reported as two separate single nucleotide changes in gnomAD, with both variants found in the same subpopulations with the same number of occurrences, and read data demonstrating that both of these SNPs occurred together in cis, in 3 cases. Therefore the variant allele was found at a frequency of 2e-05 in 251054 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2080_2081delinsTC has been reported in the literature in an individual affected with sarcoma, who also carried a BRCA2 pathogenic allele (Varga_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25712765). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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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