NM_000249.4(MLH1):c.595G>C (p.Glu199Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jan 25, 2023
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:: RCV000165198.14

Allele description [Variation Report for NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)]

NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)

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.595G>C (p.Glu199Gln)

HGVS:

NC_000003.12:g.37012017G>C
NG_007109.2:g.23668G>C
NM_000249.4:c.595G>CMANE SELECT
NM_001167617.3:c.301G>C
NM_001167618.3:c.-129G>C
NM_001167619.3:c.-129G>C
NM_001258271.2:c.595G>C
NM_001258273.2:c.-129G>C
NM_001258274.3:c.-129G>C
NM_001354615.2:c.-129G>C
NM_001354616.2:c.-129G>C
NM_001354617.2:c.-129G>C
NM_001354618.2:c.-129G>C
NM_001354619.2:c.-129G>C
NM_001354620.2:c.301G>C
NM_001354621.2:c.-222G>C
NM_001354622.2:c.-335G>C
NM_001354623.2:c.-335G>C
NM_001354624.2:c.-232G>C
NM_001354625.2:c.-232G>C
NM_001354626.2:c.-232G>C
NM_001354627.2:c.-232G>C
NM_001354628.2:c.595G>C
NM_001354629.2:c.496G>C
NM_001354630.2:c.595G>C
NP_000240.1:p.Glu199Gln
NP_000240.1:p.Glu199Gln
NP_001161089.1:p.Glu101Gln
NP_001245200.1:p.Glu199Gln
NP_001341549.1:p.Glu101Gln
NP_001341557.1:p.Glu199Gln
NP_001341558.1:p.Glu166Gln
NP_001341559.1:p.Glu199Gln
LRG_216t1:c.595G>C
LRG_216:g.23668G>C
LRG_216p1:p.Glu199Gln
NC_000003.11:g.37053508G>C
NM_000249.3:c.595G>C
p.E199Q

Protein change:

E101Q

Links:

dbSNP: rs63749887

NCBI 1000 Genomes Browser:

rs63749887

Molecular consequence:

NM_001167618.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-222G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.301G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.301G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.496G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.595G>C - 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
SCV000215910	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Feb 2, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10495924, 17510385 Citation Link,
SCV000684851	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 25, 2023)	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

SCV000215910

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Feb 2, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000684851

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jan 25, 2023)

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

Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1.

Wahlberg S, Liu T, Lindblom P, Lindblom A.

Genet Test. 1999;3(3):259-64.

PubMed [citation]

PMID:: 10495924

Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C.

Cancer Res. 2007 May 15;67(10):4595-604.

PubMed [citation]

PMID:: 17510385

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000215910.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000684851.4

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

#	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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