NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) AND not specified

Germline classification:: Benign/Likely benign (2 submissions)
Last evaluated:: Aug 15, 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:: RCV000212524.19

Allele description [Variation Report for NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)]

NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)

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.649C>T (p.Arg217Cys)

Other names:

p.R217C:CGC>TGC

HGVS:

NC_000003.12:g.37012071C>T
NG_007109.2:g.23722C>T
NM_000249.4:c.649C>TMANE SELECT
NM_001167617.3:c.355C>T
NM_001167618.3:c.-75C>T
NM_001167619.3:c.-75C>T
NM_001258271.2:c.649C>T
NM_001258273.2:c.-75C>T
NM_001258274.3:c.-75C>T
NM_001354615.2:c.-75C>T
NM_001354616.2:c.-75C>T
NM_001354617.2:c.-75C>T
NM_001354618.2:c.-75C>T
NM_001354619.2:c.-75C>T
NM_001354620.2:c.355C>T
NM_001354621.2:c.-168C>T
NM_001354622.2:c.-281C>T
NM_001354623.2:c.-281C>T
NM_001354624.2:c.-178C>T
NM_001354625.2:c.-178C>T
NM_001354626.2:c.-178C>T
NM_001354627.2:c.-178C>T
NM_001354628.2:c.649C>T
NM_001354629.2:c.550C>T
NM_001354630.2:c.649C>T
NP_000240.1:p.Arg217Cys
NP_000240.1:p.Arg217Cys
NP_001161089.1:p.Arg119Cys
NP_001245200.1:p.Arg217Cys
NP_001341549.1:p.Arg119Cys
NP_001341557.1:p.Arg217Cys
NP_001341558.1:p.Arg184Cys
NP_001341559.1:p.Arg217Cys
LRG_216t1:c.649C>T
LRG_216:g.23722C>T
LRG_216p1:p.Arg217Cys
NC_000003.11:g.37053562C>T
NM_000249.3:c.649C>T
P40692:p.Arg217Cys
p.R217C

Protein change:

R119C

Links:

UniProtKB: P40692#VAR_004449; dbSNP: rs4986984

NCBI 1000 Genomes Browser:

rs4986984

Molecular consequence:

NM_001167618.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-168C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696175	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jul 24, 2023)	germline	clinical testing	PubMed (26) [See all records that cite these PMIDs] 12810663, 18373977, 11555625, 8797773, 18069769, 17510385, 9419403, 15342696, 8581513, 11781295, 15613555, 11920458, 24933000, 25882375, 21901500, 27553368, 22136435, 16425354, 27173243, 27093186, 25338684, 28767289, 29050249, 29505604, 30850667, 31666926 Citation Link,
SCV002552435	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Aug 15, 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

SCV000696175

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Jul 24, 2023)

germline

clinical testing

PubMed (26)
[See all records that cite these PMIDs]

Citation Link,

SCV002552435

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Aug 15, 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

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]

PMID:: 12810663

The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations.

Zhao N, Zhu F, Yuan F, Haick AK, Fukushige S, Gu L, Her C.

Biochem Biophys Res Commun. 2008 May 30;370(2):338-43. doi: 10.1016/j.bbrc.2008.03.082. Epub 2008 Mar 26.

PubMed [citation]

PMID:: 18373977
PMCID:: PMC2443822

See all PubMed Citations (27)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696175.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (26)

Description

Variant summary: MLH1 c.649C>T (p.Arg217Cys) 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. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 0.00041 in 252977 control chromosomes, predominantly at a frequency of 0.0047 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.649C>T has also been reported in the literature in several individuals affected with Lynch Syndrome, who were predominantly of Asian descent and the majority of these publications only performed evaluation of MLH1 and could not rule out variants in other Lynch syndrome associated genes. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, in one publication (Sapari 2014), the variant was found in co-occurrence with another pathogenic MLH1 variant, c.790+1G>A (although it was only identified through NGS and not confirmed by Sanger sequencing). One co-occurrence with another pathogenic variant has been reported internally (BRCA2 c.1648G>T , p.Glu550X), providing supporting evidence for a benign role. Several publications reported experimental evidence evaluating an impact on protein function (Ellison 2001, Trojan 2002, Kondo 2003, Takahashi 2007, Zhao 2008, Peng 2016), showing no or only a mild effect on function. A recent study suggested based on in vitro evidence that the variant might affect splicing by affecting splicesome assembly (Rhine 2018), however earlier reports that identified the variant in patients through RNA-based direct sequencing, did not indicate any specific splicing effect (Furukawa 2002, Wang 2005); therefore, the significance of this finding is uncertain. The following publications have been ascertained in the context of this evaluation (PMID: 12810663, 18373977, 11555625, 8797773, 18069769, 17510385, 9419403, 15342696, 8581513, 11781295, 15613555, 11920458, 24933000, 25882375, 21901500, 27553368, 22136435, 16425354, 27173243, 27093186, 25338684, 28767289, 29050249, 29505604, 30850667, 31666926). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=7) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002552435.4

#	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: Nov 3, 2024

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