NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Dec 9, 2020
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:: RCV000115483.21

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)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184755	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 24, 2018)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 11555625, 11781295, 12810663, 17192056, 17510385, 17594722, 18094436, 20176959, 21155023, 21901500, 22949387, 23760103, 27487738, 28767289, 29505604 Citation Link,
SCV000689902	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Dec 8, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528765	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Dec 9, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184755

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 24, 2018)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

Citation Link,

SCV000689902

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Dec 8, 2015)

germline

clinical testing

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

SCV002528765

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Benign
(Dec 9, 2020)

germline

curation

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, curation

Citations

PubMed

Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.

Ellison AR, Lofing J, Bitter GA.

Hum Mol Genet. 2001 Sep 1;10(18):1889-900.

PubMed [citation]

PMID:: 11555625

Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.

Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G.

Gastroenterology. 2002 Jan;122(1):211-9.

PubMed [citation]

PMID:: 11781295

See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV000184755.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000689902.2

#	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

From Sema4, Sema4, SCV002528765.1

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

#	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: Jul 23, 2024

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