VCV000036557.44 - ClinVar

NM_000249.4(MLH1):c.655A>G (p.Ile219Val)

Germline

Top reviewed classifications are shown here.

Submission summary:

29 submissions

29 submitters

8 conditions

Reviewed by expert panel

No known pathogenicity

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.655A>G (p.Ile219Val)

Variation ID: 36557 Accession: VCV000036557.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37012077 (GRCh38) [ NCBI UCSC ] 3: 37053568 (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	Apr 12, 2013	Sep 29, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.655A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Ile219Val	missense
NM_001167617.3:c.361A>G	NP_001161089.1:p.Ile121Val	missense
NM_001167618.3:c.-69A>G		5 prime UTR
NM_001167619.3:c.-69A>G		5 prime UTR
NM_001258271.2:c.655A>G	NP_001245200.1:p.Ile219Val	missense
NM_001258273.2:c.-69A>G		5 prime UTR
NM_001258274.3:c.-69A>G		5 prime UTR
NM_001354615.2:c.-69A>G		5 prime UTR
NM_001354616.2:c.-69A>G		5 prime UTR
NM_001354617.2:c.-69A>G		5 prime UTR
NM_001354618.2:c.-69A>G		5 prime UTR
NM_001354619.2:c.-69A>G		5 prime UTR
NM_001354620.2:c.361A>G	NP_001341549.1:p.Ile121Val	missense
NM_001354621.2:c.-162A>G		5 prime UTR
NM_001354622.2:c.-275A>G		5 prime UTR
NM_001354623.2:c.-275A>G		5 prime UTR
NM_001354624.2:c.-172A>G		5 prime UTR
NM_001354625.2:c.-172A>G		5 prime UTR
NM_001354626.2:c.-172A>G		5 prime UTR
NM_001354627.2:c.-172A>G		5 prime UTR
NM_001354628.2:c.655A>G	NP_001341557.1:p.Ile219Val	missense
NM_001354629.2:c.556A>G	NP_001341558.1:p.Ile186Val	missense
NM_001354630.2:c.655A>G	NP_001341559.1:p.Ile219Val	missense
NC_000003.12:g.37012077A>G
NC_000003.11:g.37053568A>G
NG_007109.2:g.23728A>G
LRG_216:g.23728A>G
LRG_216t1:c.655A>G	LRG_216p1:p.Ile219Val
	P40692:p.Ile219Val

... more HGVS ... less HGVS

Protein change

I219V, I121V, I186V

Other names

Canonical SPDI

NC_000003.12:37012076: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.

0.12959 (G)

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

1000 Genomes Project 30x 0.12914

1000 Genomes Project 0.12959

Trans-Omics for Precision Medicine (TOPMed) 0.21422

The Genome Aggregation Database (gnomAD) 0.23048

Exome Aggregation Consortium (ExAC) 0.23254

The Genome Aggregation Database (gnomAD), exomes 0.23277

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.24296

Links

ClinGen: CA011410 UniProtKB: P40692#VAR_004450 dbSNP: rs1799977 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	5694	5755

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.
Lynch syndrome	Benign (3)	reviewed by expert panel	Sep 5, 2013	RCV000030230.16
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV000034548.25
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Jun 24, 2014	RCV000035355.39
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Jan 10, 2020	RCV000131385.14
Lynch syndrome 1	Benign (2)	criteria provided, single submitter	Aug 18, 2017	RCV000144603.10
Colorectal cancer, hereditary nonpolyposis, type 2	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000614686.14
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001083425.13
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001269359.9

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.
no known pathogenicity (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: SCV000106807.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comments (2): MAF >1% Converted during submission to Benign.
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001875389.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, … (more) This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725) (less)
Benign (Jan 10, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528766.1 First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604227.9 First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	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: SCV004840890.1 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)	Number of individuals with the variant: 50191 Zygosity: Homozygote, Single Heterozygote
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005245161.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Nov 04, 2014)	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: SCV000292085.1 First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303152.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: no Allele origin: germline	IntelligeneCG Accession: SCV000611716.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Benign (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781752.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jun 24, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110268.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MLH1 Number of individuals with the variant: 14 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Benign (Aug 23, 2011)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059003.5 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Comment: This variant is classified as benign based on its high frequency in the general population (rs1799977, MAF >3%). Number of individuals with the variant: 2
Benign (Mar 06, 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: SCV000443330.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Feb 01, 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: SCV000999981.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Nov 13, 2014)	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: SCV000186361.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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. (less)
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015862.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Nov 15, 2011)	no assertion criteria provided Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052897.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927690.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001958956.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
no known pathogenicity (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043321.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Benign. Number of individuals with the variant: 288 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Benign (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Lynch syndrome I Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189930.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257110.2 First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017
Benign (-)	no assertion criteria provided Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734264.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	Breast Cancer Affected status: yes Allele origin: germline	Center of Medical Genetics and Primary Health Care Accession: SCV001448700.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV000592366.2 First in ClinVar: Aug 27, 2017 Last updated: Jan 26, 2021	Comment: The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at … (more) The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977). (less) Number of individuals with the variant: 36
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906103.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919475.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969492.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085536.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as 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.

Comment:

The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977).

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MLH1	-	-	-	-
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.655A%3EG	-	-	-	-

Text-mined citations for rs1799977 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.655A>G (p.Ile219Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1799977 ...