NM_000249.4(MLH1):c.2084C>A (p.Ser695Ter) AND Lynch syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075523.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2084C>A (p.Ser695Ter)]

NM_000249.4(MLH1):c.2084C>A (p.Ser695Ter)

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.2084C>A (p.Ser695Ter)

HGVS:

NC_000003.12:g.37048998C>A
NG_007109.2:g.60649C>A
NM_000249.4:c.2084C>AMANE SELECT
NM_001167617.3:c.1790C>A
NM_001167618.3:c.1361C>A
NM_001167619.3:c.1361C>A
NM_001258271.2:c.1896+1315C>A
NM_001258273.2:c.1361C>A
NM_001258274.3:c.1361C>A
NM_001354615.2:c.1361C>A
NM_001354616.2:c.1361C>A
NM_001354617.2:c.1361C>A
NM_001354618.2:c.1361C>A
NM_001354619.2:c.1361C>A
NM_001354620.2:c.1790C>A
NM_001354621.2:c.1061C>A
NM_001354622.2:c.1061C>A
NM_001354623.2:c.1061C>A
NM_001354624.2:c.1010C>A
NM_001354625.2:c.1010C>A
NM_001354626.2:c.1010C>A
NM_001354627.2:c.1010C>A
NM_001354628.2:c.1991C>A
NM_001354629.2:c.1985C>A
NM_001354630.2:c.1919C>A
NP_000240.1:p.Ser695Ter
NP_000240.1:p.Ser695Ter
NP_001161089.1:p.Ser597Ter
NP_001161090.1:p.Ser454Ter
NP_001161091.1:p.Ser454Ter
NP_001245202.1:p.Ser454Ter
NP_001245203.1:p.Ser454Ter
NP_001341544.1:p.Ser454Ter
NP_001341545.1:p.Ser454Ter
NP_001341546.1:p.Ser454Ter
NP_001341547.1:p.Ser454Ter
NP_001341548.1:p.Ser454Ter
NP_001341549.1:p.Ser597Ter
NP_001341550.1:p.Ser354Ter
NP_001341551.1:p.Ser354Ter
NP_001341552.1:p.Ser354Ter
NP_001341553.1:p.Ser337Ter
NP_001341554.1:p.Ser337Ter
NP_001341555.1:p.Ser337Ter
NP_001341556.1:p.Ser337Ter
NP_001341557.1:p.Ser664Ter
NP_001341558.1:p.Ser662Ter
NP_001341559.1:p.Ser640Ter
LRG_216t1:c.2084C>A
LRG_216:g.60649C>A
LRG_216p1:p.Ser695Ter
NC_000003.11:g.37090489C>A
NM_000249.3:c.2084C>A

Protein change:

S337*

Links:

dbSNP: rs63749995

NCBI 1000 Genomes Browser:

rs63749995

Molecular consequence:

NM_001258271.2:c.1896+1315C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2084C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1790C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1361C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1790C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1061C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1061C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1061C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1010C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1010C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1010C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1010C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.1991C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.1985C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.1919C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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protein phosphatase 1F [Capsaspora owczarzaki ATCC 30864]
protein phosphatase 1F [Capsaspora owczarzaki ATCC 30864]
gi|320165345|gb|EFW42244.1||gnl|WGS |CAOG_07629T0

Protein
PREDICTED: Arabidopsis lyrata subsp. lyrata beta-glucosidase 10 (LOC9303552), tr...
PREDICTED: Arabidopsis lyrata subsp. lyrata beta-glucosidase 10 (LOC9303552), transcript variant X1, mRNA
gi|1191004396|ref|XM_002867434.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106519	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000696144	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 27, 2016)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106519

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000696144

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Oct 27, 2016)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx

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, research

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106519.3

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

Description

Coding sequence variation resulting in a stop codon

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696144.1

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

Description

Variant summary: The MLH1 c.2084C>A (p.Ser695X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.: p.Trp714X, p.His727fsX55). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120582 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.

#	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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