VCV000089590.64 - ClinVar

NM_000249.4(MLH1):c.-28A>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(4); Likely benign(7)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.-28A>G

Variation ID: 89590 Accession: VCV000089590.64

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 36993520 (GRCh38) [ NCBI UCSC ] 3: 37035011 (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	Mar 24, 2015	Oct 20, 2024	Jan 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.-28A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NM_001167617.3:c.-544A>G		5 prime UTR
NM_001167618.3:c.-973A>G		5 prime UTR
NM_001167619.3:c.-886A>G		5 prime UTR
NM_001258271.2:c.-28A>G		5 prime UTR
NM_001258273.2:c.-660A>G		5 prime UTR
NM_001258274.3:c.-1123A>G		5 prime UTR
NM_001354615.2:c.-654A>G		5 prime UTR
NM_001354616.2:c.-654A>G		5 prime UTR
NM_001354617.2:c.-746A>G		5 prime UTR
NM_001354618.2:c.-978A>G		5 prime UTR
NM_001354619.2:c.-1102A>G		5 prime UTR
NM_001354620.2:c.-312A>G		5 prime UTR
NM_001354621.2:c.-1071A>G		5 prime UTR
NM_001354622.2:c.-1184A>G		5 prime UTR
NM_001354623.2:c.-1093A>G		5 prime UTR
NM_001354624.2:c.-854A>G		5 prime UTR
NM_001354625.2:c.-752A>G		5 prime UTR
NM_001354626.2:c.-849A>G		5 prime UTR
NM_001354627.2:c.-1081A>G		5 prime UTR
NM_001354628.2:c.-28A>G		5 prime UTR
NM_001354629.2:c.-28A>G		5 prime UTR
NM_001354630.2:c.-28A>G		5 prime UTR
NC_000003.12:g.36993520A>G
NC_000003.11:g.37035011A>G
NG_007109.2:g.5171A>G
NG_008418.1:g.4785T>C
LRG_216:g.5171A>G
LRG_216t1:c.-28A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:36993519:A:G

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.

0.00080 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00059

1000 Genomes Project 30x 0.00062

1000 Genomes Project 0.00080

The Genome Aggregation Database (gnomAD) 0.00110

Links

ClinGen: CA009523 dbSNP: rs56198082 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	5690	5751

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.
not specified	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Aug 15, 2023	RCV000115447.29
Colorectal cancer, hereditary nonpolyposis, type 2	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 20, 2018	RCV000662924.12
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 1, 2024	RCV000656855.30
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Oct 2, 2020	RCV001190167.5
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Dec 6, 2022	RCV001521973.9
Breast and/or ovarian cancer	Likely benign (1)	criteria provided, single submitter	Nov 11, 2022	RCV003149729.5
Hereditary cancer	Likely benign (1)	criteria provided, single submitter	Jan 23, 2024	RCV003492406.1

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.
Uncertain significance (Apr 08, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592325.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017	Publications: PubMed (5) PubMed: 16963262‚ 24689082‚ 15996210‚ 18726168‚ 22136435
Likely benign (Dec 21, 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: SCV000785872.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018	Publications: PubMed (7) PubMed: 15996210‚ 22136435‚ 18566915‚ 18726168‚ 25762362‚ 24689082‚ 16963262
Uncertain significance (Aug 20, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001308677.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Sep 02, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149356.13 First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019	Comment: Observed with MLH1 c.-7C>T and in isolation in individuals with MLH1-associated and other cancers (Lee 2005, Fredriksson 2006, Thompson 2014, Hesson 2015, Morak 2018, Lin … (more) Observed with MLH1 c.-7C>T and in isolation in individuals with MLH1-associated and other cancers (Lee 2005, Fredriksson 2006, Thompson 2014, Hesson 2015, Morak 2018, Lin 2019); Published functional studies are inconclusive: has not undergone independent functional interrogation, but when studied with MLH1 c.-7C>T, not associated with MLH1 promoter methylation and conflicting results regarding impact on MLH1 expression (Hesson 2015, Morak 2018); Case control studies suggest this variant is not associated with gastric cancer in a Chinese population (Zhi 2011); Observed in 0.1665% (471/282862) of alleles in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30850667, 25762362, 24689082, 11726306, 22136435, 16963262, 15996210, 18726168, 18566915, 26888055, 29472279, 31386297) (less)
Benign (Oct 02, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528736.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552410.4 First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023
Likely benign (Nov 11, 2022)	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: SCV003838265.2 First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024
Benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000539630.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.9% (58/6612) Finnish chromosomes (less) Method: Genome/Exome Filtration
Likely benign (Nov 15, 2018)	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: SCV001357593.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Jul 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002072436.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Sep 20, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002773900.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (10) PubMed: 11726306‚ 15996210‚ 18726168‚ 18566915‚ 22136435‚ 25762362‚ 16963262‚ 31386297‚ 30850667‚ 29472279
Uncertain significance (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691838.2 First in ClinVar: Feb 19, 2018 Last updated: Jan 26, 2024	Publications: PubMed (2) PubMed: 25762362‚ 29472279 Comment: BS1 Number of individuals with the variant: 3
Likely benign (Jan 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000837989.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024
Benign (Dec 06, 2022)	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: SCV001731416.3 First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024
Likely benign (Jan 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: SCV001153830.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: MLH1: BP4, BS1 Number of individuals with the variant: 4
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074987.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Uncertain significance and reported on 09-02-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 09-02-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Myopia (present) , Anxiety (present) Age: 20-29 years Sex: female Testing laboratory: Genetics Laboratory, Trillium Health Partners,Trillium Health Partners, Credit Valley Hospital Site Date variant was reported to submitter: 2020-09-02 Testing laboratory interpretation: Uncertain significance
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Observed with MLH1 c.-7C>T and in isolation in individuals with MLH1-associated and other cancers (Lee 2005, Fredriksson 2006, Thompson 2014, Hesson 2015, Morak 2018, Lin 2019); Published functional studies are inconclusive: has not undergone independent functional interrogation, but when studied with MLH1 c.-7C>T, not associated with MLH1 promoter methylation and conflicting results regarding impact on MLH1 expression (Hesson 2015, Morak 2018); Case control studies suggest this variant is not associated with gastric cancer in a Chinese population (Zhi 2011); Observed in 0.1665% (471/282862) of alleles in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30850667, 25762362, 24689082, 11726306, 22136435, 16963262, 15996210, 18726168, 18566915, 26888055, 29472279, 31386297)

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.9% (58/6612) Finnish chromosomes

Comment:

Variant interpreted as Uncertain significance and reported on 09-02-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.	Kiyozumi Y	Cancer medicine	2019	PMID: 31386297
Germline susceptibility variants impact clinical outcome and therapeutic strategies for stage III colorectal cancer.	Lin PC	Scientific reports	2019	PMID: 30850667
Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.	Morak M	Journal of medical genetics	2018	PMID: 29472279
Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.	Hesson LB	Human mutation	2015	PMID: 25762362
A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes.	Hansen MF	Molecular genetics & genomic medicine	2014	PMID: 24689082
The MLH1 2101C>A (Q701K) variant increases the risk of gastric cancer in Chinese males.	Zhi W	BMC gastroenterology	2011	PMID: 22136435
Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore.	Yap HL	Familial cancer	2009	PMID: 18726168
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.	Nilbert M	Familial cancer	2009	PMID: 18566915
Identification of germline MLH1 alterations in familial prostate cancer.	Fredriksson H	European journal of cancer (Oxford, England : 1990)	2006	PMID: 16963262
Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia.	Lee SC	Clinical genetics	2005	PMID: 15996210
Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms?	Müller-Koch Y	European journal of medical research	2001	PMID: 11726306
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Text-mined citations for rs56198082 ...

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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.-28A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56198082 ...