NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr) AND Lynch syndrome

Germline classification:: Pathogenic (3 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:: RCV000075598.6

Allele description [Variation Report for NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr)]

NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr)

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.230G>A (p.Cys77Tyr)

HGVS:

NC_000003.12:g.37000977G>A
NG_007109.2:g.12628G>A
NM_000249.4:c.230G>AMANE SELECT
NM_001167617.3:c.-60G>A
NM_001167618.3:c.-494G>A
NM_001167619.3:c.-402G>A
NM_001258271.2:c.230G>A
NM_001258273.2:c.-494G>A
NM_001258274.3:c.-494G>A
NM_001354615.2:c.-397G>A
NM_001354616.2:c.-402G>A
NM_001354617.2:c.-494G>A
NM_001354618.2:c.-494G>A
NM_001354619.2:c.-494G>A
NM_001354620.2:c.-60G>A
NM_001354621.2:c.-587G>A
NM_001354622.2:c.-700G>A
NM_001354623.2:c.-700G>A
NM_001354624.2:c.-597G>A
NM_001354625.2:c.-500G>A
NM_001354626.2:c.-597G>A
NM_001354627.2:c.-597G>A
NM_001354628.2:c.230G>A
NM_001354629.2:c.208-3424G>A
NM_001354630.2:c.230G>A
NP_000240.1:p.Cys77Tyr
NP_000240.1:p.Cys77Tyr
NP_001245200.1:p.Cys77Tyr
NP_001341557.1:p.Cys77Tyr
NP_001341559.1:p.Cys77Tyr
LRG_216t1:c.230G>A
LRG_216:g.12628G>A
LRG_216p1:p.Cys77Tyr
NC_000003.11:g.37042468G>A
NM_000249.3:c.230G>A
P40692:p.Cys77Tyr

Protein change:

C77Y

Links:

UniProtKB: P40692#VAR_012904; dbSNP: rs63750437

NCBI 1000 Genomes Browser:

rs63750437

Molecular consequence:

NM_001167617.3:c.-60G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-402G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-397G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-402G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-60G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-587G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-700G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-700G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-500G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3424G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106595	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000592340	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2015)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19669161, 18383312, 21404117, 12810663, 17594722, 17510385, 24362816, 22949379, 9032648, 17210669, 25741868
SCV004835258	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9032648, 9697702, 12810663, 15849733, 17210669, 17510385, 18383312, 21404117, 25420488, 26895986, 31697235, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106595

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000592340

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2015)

germline

clinical testing

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

SCV004835258

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 10, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Comparative in silico analyses and experimental validation of novel splice site and missense mutations in the genes MLH1 and MSH2.

Betz B, Theiss S, Aktas M, Konermann C, Goecke TO, Möslein G, Schaal H, Royer-Pokora B.

J Cancer Res Clin Oncol. 2010 Jan;136(1):123-34. doi: 10.1007/s00432-009-0643-z.

PubMed [citation]

PMID:: 19669161

Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes.

Ou J, Niessen RC, Lützen A, Sijmons RH, Kleibeuker JH, de Wind N, Rasmussen LJ, Hofstra RM.

Hum Mutat. 2007 Nov;28(11):1047-54. Review.

PubMed [citation]

PMID:: 17594722

See all PubMed Citations (16)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106595.3

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

Description

Multifactorial likelihood analysis posterior probability >0.99

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592340.1

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

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

From All of Us Research Program, National Institutes of Health, SCV004835258.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces cysteine with tyrosine at codon 77 in the ATPase domain of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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