NM_000249.4(MLH1):c.199G>T (p.Gly67Trp) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 12, 2023
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:: RCV000018618.31

Allele description [Variation Report for NM_000249.4(MLH1):c.199G>T (p.Gly67Trp)]

NM_000249.4(MLH1):c.199G>T (p.Gly67Trp)

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>T (p.Gly67Trp)

HGVS:

NC_000003.12:g.36996701G>T
NG_007109.2:g.8352G>T
NG_008418.1:g.1604C>A
NM_000249.4:c.199G>TMANE SELECT
NM_001167617.3:c.-91G>T
NM_001167618.3:c.-525G>T
NM_001167619.3:c.-433G>T
NM_001258271.2:c.199G>T
NM_001258273.2:c.-517+3038G>T
NM_001258274.3:c.-670G>T
NM_001354615.2:c.-428G>T
NM_001354616.2:c.-433G>T
NM_001354617.2:c.-525G>T
NM_001354618.2:c.-525G>T
NM_001354619.2:c.-525G>T
NM_001354620.2:c.-91G>T
NM_001354621.2:c.-618G>T
NM_001354622.2:c.-731G>T
NM_001354623.2:c.-723+2811G>T
NM_001354624.2:c.-628G>T
NM_001354625.2:c.-531G>T
NM_001354626.2:c.-628G>T
NM_001354627.2:c.-628G>T
NM_001354628.2:c.199G>T
NM_001354629.2:c.199G>T
NM_001354630.2:c.199G>T
NP_000240.1:p.Gly67Trp
NP_000240.1:p.Gly67Trp
NP_001245200.1:p.Gly67Trp
NP_001341557.1:p.Gly67Trp
NP_001341558.1:p.Gly67Trp
NP_001341559.1:p.Gly67Trp
LRG_216t1:c.199G>T
LRG_216:g.8352G>T
LRG_216p1:p.Gly67Trp
NC_000003.11:g.37038192G>T
NM_000249.3:c.199G>T
P40692:p.Gly67Trp

Protein change:

G67W; GLY67TRP

Links:

UniProtKB: P40692#VAR_012903; OMIM: 120436.0011; dbSNP: rs63750206

NCBI 1000 Genomes Browser:

rs63750206

Molecular consequence:

NM_001167617.3:c.-91G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-525G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-433G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-670G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-428G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-433G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-525G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-525G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-525G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-91G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-618G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-731G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-628G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-531G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-628G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-628G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3038G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2811G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.199G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.199G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.199G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.199G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.199G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038901	OMIM	no assertion criteria provided	Pathogenic (Jan 15, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004187602	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jul 12, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17510385, 10480359, 9927034, 21642682 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000038901

OMIM

no assertion criteria provided

Pathogenic
(Jan 15, 1999)

germline

literature only

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

SCV004187602

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Jul 12, 2023)

unknown

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.

Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A.

Hum Genet. 1999 Jul-Aug;105(1-2):79-85.

PubMed [citation]

PMID:: 10480359

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000038901.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 affected members of a consanguineous North African family in which 11 members of multiple generations developed colorectal cancers (HNPCC2; 609310), 8 of them before the age of 50 years, Wang et al. (1999) identified a heterozygous G-to-T transversion in exon 2 of the MLH1 gene, resulting in a gly67-to-trp (G67W) substitution. Two female children who were homozygous for the mutation had early onset of hematologic neoplastic disorders, including undifferentiated non-Hodgkin malignant lymphoma, acute myeloid leukemia, and a medulloblastoma, consistent with mismatch repair cancer syndrome (MMRCS1; 276300). In addition, both sisters had clinical features of type I neurofibromatosis (NF1; 162200): one had multiple but strictly hemicorporal cafe-au-lait macules and a pseudarthrosis of the tibia, whereas the other had 9 cafe-au-lait spots. No other family member had NF1.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004187602.1

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

Description

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10480359, 9927034, 21642682]. This variant is expected to disrupt protein structure [Myriad internal data].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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