NM_000249.4(MLH1):c.793C>T (p.Arg265Cys) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV000524317.15

Allele description [Variation Report for NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)]

NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)

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.793C>T (p.Arg265Cys)

HGVS:

NC_000003.12:g.37017508C>T
NG_007109.2:g.29159C>T
NM_000249.4:c.793C>TMANE SELECT
NM_001167617.3:c.499C>T
NM_001167618.3:c.70C>T
NM_001167619.3:c.70C>T
NM_001258271.2:c.793C>T
NM_001258273.2:c.70C>T
NM_001258274.3:c.70C>T
NM_001354615.2:c.70C>T
NM_001354616.2:c.70C>T
NM_001354617.2:c.70C>T
NM_001354618.2:c.70C>T
NM_001354619.2:c.70C>T
NM_001354620.2:c.499C>T
NM_001354621.2:c.-139-2802C>T
NM_001354622.2:c.-139-2802C>T
NM_001354623.2:c.-139-2802C>T
NM_001354624.2:c.-37+2964C>T
NM_001354625.2:c.-37+2964C>T
NM_001354626.2:c.-37+2964C>T
NM_001354627.2:c.-37+2964C>T
NM_001354628.2:c.793C>T
NM_001354629.2:c.694C>T
NM_001354630.2:c.793C>T
NP_000240.1:p.Arg265Cys
NP_000240.1:p.Arg265Cys
NP_001161089.1:p.Arg167Cys
NP_001161090.1:p.Arg24Cys
NP_001161091.1:p.Arg24Cys
NP_001245200.1:p.Arg265Cys
NP_001245202.1:p.Arg24Cys
NP_001245203.1:p.Arg24Cys
NP_001341544.1:p.Arg24Cys
NP_001341545.1:p.Arg24Cys
NP_001341546.1:p.Arg24Cys
NP_001341547.1:p.Arg24Cys
NP_001341548.1:p.Arg24Cys
NP_001341549.1:p.Arg167Cys
NP_001341557.1:p.Arg265Cys
NP_001341558.1:p.Arg232Cys
NP_001341559.1:p.Arg265Cys
LRG_216t1:c.793C>T
LRG_216:g.29159C>T
LRG_216p1:p.Arg265Cys
NC_000003.11:g.37058999C>T
NM_000249.3:c.793C>T
NM_001167618.1:c.70C>T
P40692:p.Arg265Cys
uc010hgn.1:c.793C>T

Protein change:

R167C; ARG265CYS

Links:

UniProtKB: P40692#VAR_054530; OMIM: 120436.0030; dbSNP: rs63751194

NCBI 1000 Genomes Browser:

rs63751194

Molecular consequence:

NM_001354621.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000262499	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12386821, 15713769, 19419416, 20587412, 20864636, 11555625, 11781295, 17135187, 17510385, 18561205, 22736432, 26247049, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000262499

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (13)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers.

Yuen ST, Chan TL, Ho JW, Chan AS, Chung LP, Lam PW, Tse CW, Wyllie AH, Leung SY.

Oncogene. 2002 Oct 24;21(49):7585-92.

PubMed [citation]

PMID:: 12386821

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000262499.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 265 of the MLH1 protein (p.Arg265Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 11781295, 17135187, 17510385). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205, 22736432, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.

#	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: Jun 9, 2024

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