VCV000017087.45 - ClinVar

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

25 submissions

24 submitters

10 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

Variation ID: 17087 Accession: VCV000017087.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37012098 (GRCh38) [ NCBI UCSC ] 3: 37053589 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 7, 2015	Oct 20, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.676C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Arg226Ter	nonsense
NM_001167617.3:c.382C>T	NP_001161089.1:p.Arg128Ter	nonsense
NM_001167618.3:c.-48C>T		5 prime UTR
NM_001167619.3:c.-48C>T		5 prime UTR
NM_001258271.2:c.676C>T	NP_001245200.1:p.Arg226Ter	nonsense
NM_001258273.2:c.-48C>T		5 prime UTR
NM_001258274.3:c.-48C>T		5 prime UTR
NM_001354615.2:c.-48C>T		5 prime UTR
NM_001354616.2:c.-48C>T		5 prime UTR
NM_001354617.2:c.-48C>T		5 prime UTR
NM_001354618.2:c.-48C>T		5 prime UTR
NM_001354619.2:c.-48C>T		5 prime UTR
NM_001354620.2:c.382C>T	NP_001341549.1:p.Arg128Ter	nonsense
NM_001354621.2:c.-141C>T		5 prime UTR
NM_001354622.2:c.-254C>T		5 prime UTR
NM_001354623.2:c.-254C>T		5 prime UTR
NM_001354624.2:c.-151C>T		5 prime UTR
NM_001354625.2:c.-151C>T		5 prime UTR
NM_001354626.2:c.-151C>T		5 prime UTR
NM_001354627.2:c.-151C>T		5 prime UTR
NM_001354628.2:c.676C>T	NP_001341557.1:p.Arg226Ter	nonsense
NM_001354629.2:c.577C>T	NP_001341558.1:p.Arg193Ter	nonsense
NM_001354630.2:c.676C>T	NP_001341559.1:p.Arg226Ter	nonsense
NC_000003.12:g.37012098C>T
NC_000003.11:g.37053589C>T
NG_007109.2:g.23749C>T
LRG_216:g.23749C>T
LRG_216t1:c.676C>T	LRG_216p1:p.Arg226Ter

... more HGVS ... less HGVS

Protein change

R226*, R128*, R193*

Other names

p.R226*:CGA>TGA

Canonical SPDI

NC_000003.12:37012097:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA011496 OMIM: 120436.0010 dbSNP: rs63751615 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MLH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5693	5754

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000018616.35
Lynch syndrome	Pathogenic (3)	reviewed by expert panel	Sep 5, 2013	RCV000075801.7
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000115485.13
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000202205.21
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000524311.8
Lynch syndrome 1	Pathogenic (1)	no assertion criteria provided	-	RCV001093685.1
Lynch-like syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 2019	RCV001249951.1
Mismatch repair cancer syndrome 1	Pathogenic (1)	no assertion criteria provided	May 1, 2001	RCV001267883.1
Breast and/or ovarian cancer	Pathogenic (1)	criteria provided, single submitter	Sep 15, 2021	RCV003149572.2
Muir-Torré syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 21, 2022	RCV003137535.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000106813.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation resulting in a stop codon
Pathogenic (Aug 14, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917661.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (5) PubMed: 8872463‚ 26681312‚ 27601186‚ 28449805‚ 28874130 Comment: Variant summary: MLH1 c.676C>T (p.Arg226X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: MLH1 c.676C>T (p.Arg226X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Aug 22, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149394.15 First in ClinVar: May 17, 2014 Last updated: Sep 28, 2017	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27601186, 25980754, 28514183, 10874307, 21056691, 21868491, 21247423, 20924129, 20045164, 19690142, 18307539, 15655560, 9927033, 8872463, 23047549, 25525159, 17889038, 22949379, 15849733, 12624141, 21879275, 22776989, 9472100, 24344984, 24456667, 28445943, 26681312, 28449805, 28944238, 11343035, 28502729, 29478780, 28874130, 30521064, 30720243, 30262796, 29505604, 30998989, 29625052, 30217226, 32719484) (less)
Pathogenic (Nov 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761605.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muir-Torré syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807079.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated Number of individuals with the variant: 1 Clinical Features: Colon cancer (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (May 12, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601407.4 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (9) PubMed: 9927033‚ 32635641‚ 28944238‚ 17889038‚ 21247423‚ 23047549‚ 8872463‚ 28874130‚ 28449805 Comment: This variant causes the premature termination of MLH1 protein synthesis. In the published literature, this variant has been reported in individuals and families with Lynch … (more) This variant causes the premature termination of MLH1 protein synthesis. In the published literature, this variant has been reported in individuals and families with Lynch syndrome (PMIDs: 32635641 (2020), 28944238 (2017), 28874130 (2017), 21247423 (2011), 23047549 (2012)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 17889038 (2008)). The frequency of this variant in the general population, 0.000004 (1/250982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689906.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 9927033‚ 15655560‚ 15849733‚ 17889038‚ 18307539‚ 19690142‚ 20045164‚ 20924129‚ 21247423‚ 23047549‚ 24344984‚ 24362816‚ 27601186‚ 28514183‚ 28874130 Comment: This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is … (more) This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005093181.3 First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024	Comment: MLH1: PVS1, PP1:Strong, PM2, PS4:Moderate Number of individuals with the variant: 1
Pathogenic (Jul 19, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785381.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (4) PubMed: 23047549‚ 8872463‚ 27601186‚ 9927033
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580789.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PP1_STR, PS4_MOD, PM3, PM2_SUP	Number of individuals with the variant: 2 Sex: female
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838861.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (Mar 16, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018205.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003821573.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284071.8 First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 15713769‚ 24362816‚ 8872463‚ 10874307‚ 15655560‚ 15849733‚ 17889038‚ 21247423‚ 23047549‚ 24344984 Comment: This sequence change creates a premature translational stop signal (p.Arg226) in the MLH1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg226) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is present in population databases (rs63751615, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 8872463, 10874307, 15655560, 15849733, 17889038, 21247423, 23047549, 24344984). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17087). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004840892.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (15) PubMed: 9927033‚ 15655560‚ 15849733‚ 17889038‚ 18307539‚ 19690142‚ 20045164‚ 20924129‚ 21247423‚ 23047549‚ 24344984‚ 24362816‚ 27601186‚ 28514183‚ 28874130 Comment: This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is … (more) This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Aug 11, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000212825.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (25) PubMed: 15655560‚ 16769400‚ 19690142‚ 19731080‚ 20045164‚ 20052760‚ 20924129‚ 21056691‚ 21247423‚ 21868491‚ 23047549‚ 24456667‚ 27601186‚ 27606285‚ 28445943‚ 28449805‚ 28514183‚ 28874130‚ 28944238‚ 30262796‚ 30521064‚ 31118792‚ 32635641‚ 8872463‚ 9927033 Comment: The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at … (more) The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 676. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been detected in multiple families meeting Amsterdam Criteria for a clinical diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome), several with tumors demonstrating microsatellite instability and loss of MLH1 protein on immunohistochemistry (Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52; Marcos I et al. J Pediatr, 2006 Jun;148:837-9; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Chang SC et al. Surgery, 2010 May;147:720-8; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Giráldez MD et al. Clin Cancer Res, 2010 Nov;16:5402-13; Limburg PJ et al. Clin Gastroenterol Hepatol, 2011 Jun;9:497-502; Castillejo A et al. BMC Med. Genet., 2011;12:12; Pal T et al. Br J Cancer, 2012 Nov;107:1783-90; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72; Hinrichsen I et al. Mol Cancer, 2014 Jan;13:11; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Dámaso E et al. Cancers (Basel), 2020 Jul;12:). This mutation has been reported as homozygous in individuals with features of constitutional mismatch repair deficiency (CMMRD) syndrome (Ricciardone MD et al. Cancer Res, 1999 Jan;59:290-3; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404). This mutation has also been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193071.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Ding PR Lab, Sun Yat-sen University Cancer Center Accession: SCV001250867.1 First in ClinVar: May 19, 2020 Last updated: May 19, 2020	Age: 40-49 years Sex: male Geographic origin: China
Pathogenic (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	Lynch-like syndrome Affected status: yes Allele origin: somatic	Constitutional Genetics Lab, Leon Berard Cancer Center Accession: SCV001423893.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Number of individuals with the variant: 2
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	MISMATCH REPAIR CANCER SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001446362.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Publications: PubMed (2) PubMed: 9927033‚ 11343035 Comment on evidence: In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic … (more) In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic malignancy at a very early age, 2 of whom displayed signs of type I neurofibromatosis (NF1; 162200). Sequence analysis in the 3 sibs demonstrated homozygosity for a 676C-T mutation in the MLH1 gene, leading to an arg226-to-ter mutation (R226X). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents were heterozygous for the mutation and had colon cancer at an early age. The phenotype in the sibs was consistent with the mismatch repair cancer syndrome (MMRCS1; 276300), which manifests features of NF1 and hematologic malignancies. Huang et al. (2001) studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that she was heterozygous for the R226X mutation. As this mutation is 2 bp from the 3-prime end of exon 8 and might affect donor splicing, an in vitro transcription translation assay was performed and confirmed the presence of the truncated peptide, which lacked the critical PMS2-binding regions at its C terminus. (less)
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038899.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 28, 2020	Publications: PubMed (2) PubMed: 9927033‚ 11343035 Comment on evidence: In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic … (more) In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic malignancy at a very early age, 2 of whom displayed signs of type I neurofibromatosis (NF1; 162200). Sequence analysis in the 3 sibs demonstrated homozygosity for a 676C-T mutation in the MLH1 gene, leading to an arg226-to-ter mutation (R226X). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents were heterozygous for the mutation and had colon cancer at an early age. The phenotype in the sibs was consistent with the mismatch repair cancer syndrome (MMRCS1; 276300), which manifests features of NF1 and hematologic malignancies. Huang et al. (2001) studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that she was heterozygous for the R226X mutation. As this mutation is 2 bp from the 3-prime end of exon 8 and might affect donor splicing, an in vitro transcription translation assay was performed and confirmed the presence of the truncated peptide, which lacked the critical PMS2-binding regions at its C terminus. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740166.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: research	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257111.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Number of individuals with the variant: 1
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552418.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Number of individuals with the variant: 2
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953289.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

Variant summary: MLH1 c.676C>T (p.Arg226X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27601186, 25980754, 28514183, 10874307, 21056691, 21868491, 21247423, 20924129, 20045164, 19690142, 18307539, 15655560, 9927033, 8872463, 23047549, 25525159, 17889038, 22949379, 15849733, 12624141, 21879275, 22776989, 9472100, 24344984, 24456667, 28445943, 26681312, 28449805, 28944238, 11343035, 28502729, 29478780, 28874130, 30521064, 30720243, 30262796, 29505604, 30998989, 29625052, 30217226, 32719484)

Comment:

This variant causes the premature termination of MLH1 protein synthesis. In the published literature, this variant has been reported in individuals and families with Lynch syndrome (PMIDs: 32635641 (2020), 28944238 (2017), 28874130 (2017), 21247423 (2011), 23047549 (2012)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 17889038 (2008)). The frequency of this variant in the general population, 0.000004 (1/250982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, this variant is classified as pathogenic.

Comment:

This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg226*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is present in population databases (rs63751615, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 8872463, 10874307, 15655560, 15849733, 17889038, 21247423, 23047549, 24344984). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17087). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 676. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been detected in multiple families meeting Amsterdam Criteria for a clinical diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome), several with tumors demonstrating microsatellite instability and loss of MLH1 protein on immunohistochemistry (Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52; Marcos I et al. J Pediatr, 2006 Jun;148:837-9; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Chang SC et al. Surgery, 2010 May;147:720-8; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Giráldez MD et al. Clin Cancer Res, 2010 Nov;16:5402-13; Limburg PJ et al. Clin Gastroenterol Hepatol, 2011 Jun;9:497-502; Castillejo A et al. BMC Med. Genet., 2011;12:12; Pal T et al. Br J Cancer, 2012 Nov;107:1783-90; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72; Hinrichsen I et al. Mol Cancer, 2014 Jan;13:11; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Dámaso E et al. Cancers (Basel), 2020 Jul;12:). This mutation has been reported as homozygous in individuals with features of constitutional mismatch repair deficiency (CMMRD) syndrome (Ricciardone MD et al. Cancer Res, 1999 Jan;59:290-3; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404). This mutation has also been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals.	Dámaso E	Cancers	2020	PMID: 32635641
Mutation spectrum of germline cancer susceptibility genes among unselected Chinese colorectal cancer patients.	Gong R	Cancer management and research	2019	PMID: 31118792
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.	Jiang W	International journal of cancer	2019	PMID: 30521064
Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility.	Quezada Urban R	Cancers	2018	PMID: 30262796
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.	DeRycke MS	Molecular genetics & genomic medicine	2017	PMID: 28944238
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.	Rossi BM	BMC cancer	2017	PMID: 28874130
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome.	Espenschied CR	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28514183
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome.	Sunga AY	Cancer genetics	2017	PMID: 28449805
A molecular inversion probe-based next-generation sequencing panel to detect germline mutations in Chinese early-onset colorectal cancer patients.	Zhang J	Oncotarget	2017	PMID: 28445943
MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome.	Dominguez-Valentin M	Frontiers in oncology	2016	PMID: 27606285
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.	Lagerstedt-Robinson K	Oncology reports	2016	PMID: 27601186
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1.	Hinrichsen I	Molecular cancer	2014	PMID: 24456667
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Mutation spectrum in South American Lynch syndrome families.	Dominguez-Valentin M	Hereditary cancer in clinical practice	2013	PMID: 24344984
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.	Pal T	British journal of cancer	2012	PMID: 23047549
Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer.	Pérez-Carbonell L	Gut	2012	PMID: 21868491
Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome.	Castillejo A	BMC medical genetics	2011	PMID: 21247423
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.	Limburg PJ	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2011	PMID: 21056691
MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer.	Giráldez MD	Clinical cancer research : an official journal of the American Association for Cancer Research	2010	PMID: 20924129
Microsatellite instability in the peripheral blood leukocytes of HNPCC patients.	Coolbaugh-Murphy MI	Human mutation	2010	PMID: 20052760
Taiwan hospital-based detection of Lynch syndrome distinguishes 2 types of microsatellite instabilities in colorectal cancers.	Chang SC	Surgery	2010	PMID: 20045164
Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis.	Jasperson KW	Familial cancer	2010	PMID: 19731080
Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases.	Mueller J	Cancer research	2009	PMID: 19690142
Clinical features and mismatch repair genes analyses of Chinese suspected hereditary non-polyposis colorectal cancer: a cost-effective screening strategy proposal.	Yan HL	Cancer science	2008	PMID: 18307539
Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia.	Alotaibi H	Mutation research	2008	PMID: 17889038
Mutations in the DNA mismatch repair gene MLH1 associated with early-onset colon cancer.	Marcos I	The Journal of pediatrics	2006	PMID: 16769400
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.	Mangold E	International journal of cancer	2005	PMID: 15849733
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.	Casey G	JAMA	2005	PMID: 15713769
hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients.	Apessos A	British journal of cancer	2005	PMID: 15655560
Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer.	Huang SC	The Journal of pediatrics	2001	PMID: 11343035
Evaluation of enzymatic mutation detectiontrade mark in hereditary nonpolyposis colorectal cancer.	Otway R	Human mutation	2000	PMID: 10874307
Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1.	Ricciardone MD	Cancer research	1999	PMID: 9927033
Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.	Moslein G	Human molecular genetics	1996	PMID: 8872463
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.676C%3ET	-	-	-	-
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Text-mined citations for rs63751615 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63751615 ...