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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 8, 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:: RCV004003719.2

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]

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
SCV004843271	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25712765, 33753878, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004843271

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 8, 2024)

germline

clinical testing

PubMed (3)
[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	4	not provided	not provided	108544	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

High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer.

Kim JE, Choi J, Sung CO, Hong YS, Kim SY, Lee H, Kim TW, Kim JI.

Exp Mol Med. 2021 Mar;53(3):446-456. doi: 10.1038/s12276-021-00583-1. Epub 2021 Mar 22.

PubMed [citation]

PMID:: 33753878
PMCID:: PMC8080557

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004843271.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). This variant has not been identified 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		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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