NM_000249.4(MLH1):c.199G>A (p.Gly67Arg) AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 11, 2021
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:: RCV001290649.1

Allele description [Variation Report for NM_000249.4(MLH1):c.199G>A (p.Gly67Arg)]

NM_000249.4(MLH1):c.199G>A (p.Gly67Arg)

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.199G>A (p.Gly67Arg)

Other names:

p.G67R:GGG>AGG

HGVS:

NC_000003.12:g.36996701G>A
NG_007109.2:g.8352G>A
NG_008418.1:g.1604C>T
NM_000249.4:c.199G>AMANE SELECT
NM_001167617.3:c.-91G>A
NM_001167618.3:c.-525G>A
NM_001167619.3:c.-433G>A
NM_001258271.2:c.199G>A
NM_001258273.2:c.-517+3038G>A
NM_001258274.3:c.-670G>A
NM_001354615.2:c.-428G>A
NM_001354616.2:c.-433G>A
NM_001354617.2:c.-525G>A
NM_001354618.2:c.-525G>A
NM_001354619.2:c.-525G>A
NM_001354620.2:c.-91G>A
NM_001354621.2:c.-618G>A
NM_001354622.2:c.-731G>A
NM_001354623.2:c.-723+2811G>A
NM_001354624.2:c.-628G>A
NM_001354625.2:c.-531G>A
NM_001354626.2:c.-628G>A
NM_001354627.2:c.-628G>A
NM_001354628.2:c.199G>A
NM_001354629.2:c.199G>A
NM_001354630.2:c.199G>A
NP_000240.1:p.Gly67Arg
NP_000240.1:p.Gly67Arg
NP_001245200.1:p.Gly67Arg
NP_001341557.1:p.Gly67Arg
NP_001341558.1:p.Gly67Arg
NP_001341559.1:p.Gly67Arg
LRG_216t1:c.199G>A
LRG_216:g.8352G>A
LRG_216p1:p.Gly67Arg
NC_000003.11:g.37038192G>A
NM_000249.3:c.199G>A
P40692:p.Gly67Arg
p.G67R

Protein change:

G67R

Links:

UniProtKB: P40692#VAR_004439; dbSNP: rs63750206

NCBI 1000 Genomes Browser:

rs63750206

Molecular consequence:

NM_001167617.3:c.-91G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-433G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-670G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-428G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-433G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-91G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-618G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-731G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-531G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3038G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2811G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

Recent activity

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zinc finger protein ZAT1-like [Cucurbita maxima]
zinc finger protein ZAT1-like [Cucurbita maxima]
gi|1280981313|ref|XP_023003920.1|

Protein
zinc finger protein ZAT4-like [Cucurbita pepo subsp. pepo]
zinc finger protein ZAT4-like [Cucurbita pepo subsp. pepo]
gi|1333110341|ref|XP_023529228.1|

Protein
hypothetical protein RHGRI_011905 [Rhododendron griersonianum]
hypothetical protein RHGRI_011905 [Rhododendron griersonianum]
gi|2028815331|gb|KAG5554202.1||gnl| ACTNZ|Rhgri04G0262300.1

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001478775	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 11, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16395668, 16083711, 21642682, 21404117, 24362816, 22753075, 30504929, 31494577, 15563510, 18337503, 32849802 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478775

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 11, 2021)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

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

Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]

PMID:: 16395668

Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.

Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lönnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes AM, Peltomäki P, Kohonen-Ccorish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, Nyström M.

Gastroenterology. 2005 Aug;129(2):537-49.

PubMed [citation]

PMID:: 16083711

See all PubMed Citations (11)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: MLH1 c.199G>A (p.Gly67Arg) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes (gnomAD). c.199G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome, including families that fulfilled the Amsterdam I criteria (e.g. Alazzouzi_2005, Hardt_2011, Bonadona_2011, Gonzalez-Acosta_2020 and in the InSiGHT database); in several cases a microsatellite instable tumor and the loss of the MLH1 (with or without the loss of PMS2) protein was noted. These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated that variant had no impact on splicing (e.g. Auclair_2006), and the variant protein had normal interaction with PMS2, however it had decreased expression, impaired subcellular localization, and decreased repair activity compared to wild type (e.g. Raevaara_2005, Andersen_2012, Drost_2019). In addition, knock-in mice carrying the variant in homozygous state had a strong cancer predisposition phenotype (Avdievich 2008). Ten submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2013, and all of them classified the variant as pathogenic (n=9; including the expert panel) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as 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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