NM_000249.4(MLH1):c.52C>T (p.Arg18Cys) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 6, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000410307.8

Allele description [Variation Report for NM_000249.4(MLH1):c.52C>T (p.Arg18Cys)]

NM_000249.4(MLH1):c.52C>T (p.Arg18Cys)

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.52C>T (p.Arg18Cys)

HGVS:

NC_000003.12:g.36993599C>T
NG_007109.2:g.5250C>T
NG_008418.1:g.4706G>A
NM_000249.4:c.52C>TMANE SELECT
NM_001167617.3:c.-465C>T
NM_001167618.3:c.-894C>T
NM_001167619.3:c.-807C>T
NM_001258271.2:c.52C>T
NM_001258273.2:c.-581C>T
NM_001258274.3:c.-1044C>T
NM_001354615.2:c.-575C>T
NM_001354616.2:c.-575C>T
NM_001354617.2:c.-667C>T
NM_001354618.2:c.-899C>T
NM_001354619.2:c.-1023C>T
NM_001354620.2:c.-233C>T
NM_001354621.2:c.-992C>T
NM_001354622.2:c.-1105C>T
NM_001354623.2:c.-1014C>T
NM_001354624.2:c.-775C>T
NM_001354625.2:c.-673C>T
NM_001354626.2:c.-770C>T
NM_001354627.2:c.-1002C>T
NM_001354628.2:c.52C>T
NM_001354629.2:c.52C>T
NM_001354630.2:c.52C>T
NP_000240.1:p.Arg18Cys
NP_000240.1:p.Arg18Cys
NP_001245200.1:p.Arg18Cys
NP_001341557.1:p.Arg18Cys
NP_001341558.1:p.Arg18Cys
NP_001341559.1:p.Arg18Cys
LRG_216t1:c.52C>T
LRG_216:g.5250C>T
LRG_216p1:p.Arg18Cys
NC_000003.11:g.37035090C>T
NM_000249.3:c.52C>T
P40692:p.Arg18Cys
p.R18C

Protein change:

R18C

Links:

UniProtKB: P40692#VAR_022663; dbSNP: rs367654552

NCBI 1000 Genomes Browser:

rs367654552

Molecular consequence:

NM_001167617.3:c.-465C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-894C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-807C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-581C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1044C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-575C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-575C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-667C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-899C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1023C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-233C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-992C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1105C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1014C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-775C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-673C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-770C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1002C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.52C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.52C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.52C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.52C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.52C>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
SCV000489172	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Sep 9, 2016)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21404117, 24728327, 14635101, 22949387, 25980754 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001482846	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 6, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004018146	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 14, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000489172

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Sep 9, 2016)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV001482846

Baylor Genetics - CSER-TexasKidsCanSeq

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 6, 2024)

unknown

clinical testing

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

SCV004018146

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely benign
(Mar 14, 2023)

unknown

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000489172.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001482846.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004018146.1

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

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	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: Oct 20, 2024

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