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NM_000249.4(MLH1):c.595G>C (p.Glu199Gln) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Mar 21, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000663260.5

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:
Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:
COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000786488Counsyl
criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))		Uncertain significance
(May 11, 2018) 		unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV004018147Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))		Likely benign
(Mar 14, 2023) 		unknownclinical testing

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

Citation Link,

SCV004193015Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 21, 2023) 		unknownclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).

Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM.

Hum Mutat. 2008 Jun;29(6):852-60. doi: 10.1002/humu.20735.

PubMed [citation]
PMID:
18383312

Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase.

Guarné A, Junop MS, Yang W.

EMBO J. 2001 Oct 1;20(19):5521-31.

PubMed [citation]
PMID:
11574484
PMCID:
PMC125661
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000786488.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Genetics, Inc., SCV004018147.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004193015.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024