VCV000089959.18 - ClinVar

NM_000249.4(MLH1):c.1961C>T (p.Pro654Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

10 submissions

10 submitters

7 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.1961C>T (p.Pro654Leu)

Variation ID: 89959 Accession: VCV000089959.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37048581 (GRCh38) [ NCBI UCSC ] 3: 37090072 (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 8, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1961C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Pro654Leu	missense
NM_001167617.3:c.1667C>T	NP_001161089.1:p.Pro556Leu	missense
NM_001167618.3:c.1238C>T	NP_001161090.1:p.Pro413Leu	missense
NM_001167619.3:c.1238C>T	NP_001161091.1:p.Pro413Leu	missense
NM_001258271.2:c.1896+898C>T		intron variant
NM_001258273.2:c.1238C>T	NP_001245202.1:p.Pro413Leu	missense
NM_001258274.3:c.1238C>T	NP_001245203.1:p.Pro413Leu	missense
NM_001354615.2:c.1238C>T	NP_001341544.1:p.Pro413Leu	missense
NM_001354616.2:c.1238C>T	NP_001341545.1:p.Pro413Leu	missense
NM_001354617.2:c.1238C>T	NP_001341546.1:p.Pro413Leu	missense
NM_001354618.2:c.1238C>T	NP_001341547.1:p.Pro413Leu	missense
NM_001354619.2:c.1238C>T	NP_001341548.1:p.Pro413Leu	missense
NM_001354620.2:c.1667C>T	NP_001341549.1:p.Pro556Leu	missense
NM_001354621.2:c.938C>T	NP_001341550.1:p.Pro313Leu	missense
NM_001354622.2:c.938C>T	NP_001341551.1:p.Pro313Leu	missense
NM_001354623.2:c.938C>T	NP_001341552.1:p.Pro313Leu	missense
NM_001354624.2:c.887C>T	NP_001341553.1:p.Pro296Leu	missense
NM_001354625.2:c.887C>T	NP_001341554.1:p.Pro296Leu	missense
NM_001354626.2:c.887C>T	NP_001341555.1:p.Pro296Leu	missense
NM_001354627.2:c.887C>T	NP_001341556.1:p.Pro296Leu	missense
NM_001354628.2:c.1897-323C>T		intron variant
NM_001354629.2:c.1862C>T	NP_001341558.1:p.Pro621Leu	missense
NM_001354630.2:c.1796C>T	NP_001341559.1:p.Pro599Leu	missense
NC_000003.12:g.37048581C>T
NC_000003.11:g.37090072C>T
NG_007109.2:g.60232C>T
LRG_216:g.60232C>T
LRG_216t1:c.1961C>T	LRG_216p1:p.Pro654Leu
	P40692:p.Pro654Leu

... more HGVS ... less HGVS

Protein change

P654L, P413L, P313L, P556L, P599L, P621L, P296L

Other names

Canonical SPDI

NC_000003.12:37048580: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.

Links

ClinGen: CA007789 UniProtKB: P40692#VAR_043431 dbSNP: rs63750726 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.
Lynch syndrome	Pathogenic (1)	reviewed by expert panel	Sep 5, 2013	RCV000075439.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 15, 2024	RCV000215855.5
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Feb 18, 2021	RCV001201909.5
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 10, 2021	RCV001554328.1
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2024	RCV002415524.3
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 24, 2023	RCV002463635.3
MLH1-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 15, 2024	RCV004724792.1

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: SCV000106436.3 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: Multifactorial likelihood analysis posterior probability >0.99
Pathogenic (Jun 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758589.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PM2, PP1, PS3, PM1, PS4
Pathogenic (Jul 24, 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: SCV004186318.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (2) PubMed: 23403630‚ 27363726 Comment: This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [Myriad internal … (more) This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. (less)
Pathogenic (Jul 11, 2023)	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: SCV004192971.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Apr 05, 2024)	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: SCV002722155.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (7) PubMed: 16083711‚ 17510385‚ 20020535‚ 21120944‚ 21404117‚ 23403630‚ 28643016 Comment: The p.P654L pathogenic mutation (also known as c.1961C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at … (more) The p.P654L pathogenic mutation (also known as c.1961C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1961. The proline at codon 654 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with Lynch syndrome, including those whose tumors demonstrated microsatellite instability and/or loss of MLH1 protein expression by IHC (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49; Alqahtani M et al. Fam. Cancer, 2018 04;17:197-203). In one meta-analysis, this mutation was detected in 11 unrelated families, nine of whom fulfilled Amsterdam II criteria (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84). Analysis of the mutant protein in bacterial plasmid vectors demonstrated decreased expression of MLH1 and PMS2; however, MMR efficiency was comparable to wild type (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49). Similar results were seen in yeast (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). Additional functional assays have shown reduced protein expression in mammalian cells (Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41) as well as 0% interaction with PMS2 and 0% dominant negative mutator effect compared to wild type (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Takahashi M et al. Cancer Res, 2007 May;67:4595-604). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447878.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Ovarian neoplasm (present) Sex: female
Pathogenic (Feb 18, 2021)	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: SCV001373001.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 21404117‚ 16083711‚ 20533529‚ 17510385 Comment: This sequence change replaces proline with leucine at codon 654 of the MLH1 protein (p.Pro654Leu). The proline residue is highly conserved and there is a … (more) This sequence change replaces proline with leucine at codon 654 of the MLH1 protein (p.Pro654Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MLH1 protein function (PMID: 21404117, 16083711, 20533529, 17510385). This variant has been observed in individual(s) with Lynch syndrome (PMID: 21404117, 16083711). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89959). (less)
Pathogenic (Apr 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279084.11 First in ClinVar: May 29, 2016 Last updated: Sep 16, 2024	Comment: Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 16083711, 21387278, 21404117, 24728189, 29025352); Published functional studies … (more) Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 16083711, 21387278, 21404117, 24728189, 29025352); Published functional studies demonstrate a damaging effect: decreased MLH1 expression, decreased stability, reduced interaction with PMS2, disruption of protein localization, and most studies demonstrating reduced mismatch repair activity (PMID: 16083711, 17510385, 17210669, 20020535, 20533529, 21404117, 22753075, 23403630); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16083711, 22753075, 20533529, 18951446, 17370310, 17192056, 16995940, 24728189, 24362816, 22949387, 21120944, 19669161, 17594722, 17210669, 15849733, 21387278, 23403630, 32658311, 29025352, 20020535, 17510385, 12799449, 36356413, 21404117) (less)
Pathogenic (Aug 10, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001775544.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: Invasive breast carcinoma ER: + , PR: + , HER2: 0 , KI67%:40 Age: 40-49 years Sex: female
Pathogenic (Jun 15, 2024)	no assertion criteria provided Method: clinical testing	MLH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005336039.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MLH1 c.1961C>T variant is predicted to result in the amino acid substitution p.Pro654Leu. This variant was reported in multiple individuals with Lynch syndrome (Raevaara … (more) The MLH1 c.1961C>T variant is predicted to result in the amino acid substitution p.Pro654Leu. This variant was reported in multiple individuals with Lynch syndrome (Raevaara et al. 2005. PubMed ID: 16083711; Kansikas et al. 2011. PubMed ID: 21120944; Hardt et al. 2011. PubMed ID: 21404117; Andersen et al. 2012. PubMed ID: 22753075; Song et al. 2014. PubMed ID: 24728189; Akcay et al. 2020. PubMed ID: 32658311; Alqahtani et al. 2018. PubMed ID: 28643016). Functional studies have shown this variant affects protein function (Hardt et al. 2011. PubMed ID: 21404117; Raevaara et al. 2005. PubMed ID: 16083711; Kosinski et al. 2010. PubMed ID: 20533529; Takahashi et al. 2007. PubMed ID: 17510385; Hinrichsen et al. 2013. PubMed ID: 23403630; Wanat et al. 2007. PubMed ID: 17210669; Ou et al. 2007. PubMed ID: 17594722; Drost et al. 2010. PubMed ID: 20020535). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89959/). This variant is interpreted as pathogenic. (less)

Comment:

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].

Comment:

The p.P654L pathogenic mutation (also known as c.1961C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1961. The proline at codon 654 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with Lynch syndrome, including those whose tumors demonstrated microsatellite instability and/or loss of MLH1 protein expression by IHC (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49; Alqahtani M et al. Fam. Cancer, 2018 04;17:197-203). In one meta-analysis, this mutation was detected in 11 unrelated families, nine of whom fulfilled Amsterdam II criteria (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84). Analysis of the mutant protein in bacterial plasmid vectors demonstrated decreased expression of MLH1 and PMS2; however, MMR efficiency was comparable to wild type (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49). Similar results were seen in yeast (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). Additional functional assays have shown reduced protein expression in mammalian cells (Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41) as well as 0% interaction with PMS2 and 0% dominant negative mutator effect compared to wild type (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Takahashi M et al. Cancer Res, 2007 May;67:4595-604). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces proline with leucine at codon 654 of the MLH1 protein (p.Pro654Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MLH1 protein function (PMID: 21404117, 16083711, 20533529, 17510385). This variant has been observed in individual(s) with Lynch syndrome (PMID: 21404117, 16083711). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89959).

Comment:

Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 16083711, 21387278, 21404117, 24728189, 29025352); Published functional studies demonstrate a damaging effect: decreased MLH1 expression, decreased stability, reduced interaction with PMS2, disruption of protein localization, and most studies demonstrating reduced mismatch repair activity (PMID: 16083711, 17510385, 17210669, 20020535, 20533529, 21404117, 22753075, 23403630); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16083711, 22753075, 20533529, 18951446, 17370310, 17192056, 16995940, 24728189, 24362816, 22949387, 21120944, 19669161, 17594722, 17210669, 15849733, 21387278, 23403630, 32658311, 29025352, 20020535, 17510385, 12799449, 36356413, 21404117)

Comment:

The MLH1 c.1961C>T variant is predicted to result in the amino acid substitution p.Pro654Leu. This variant was reported in multiple individuals with Lynch syndrome (Raevaara et al. 2005. PubMed ID: 16083711; Kansikas et al. 2011. PubMed ID: 21120944; Hardt et al. 2011. PubMed ID: 21404117; Andersen et al. 2012. PubMed ID: 22753075; Song et al. 2014. PubMed ID: 24728189; Akcay et al. 2020. PubMed ID: 32658311; Alqahtani et al. 2018. PubMed ID: 28643016). Functional studies have shown this variant affects protein function (Hardt et al. 2011. PubMed ID: 21404117; Raevaara et al. 2005. PubMed ID: 16083711; Kosinski et al. 2010. PubMed ID: 20533529; Takahashi et al. 2007. PubMed ID: 17510385; Hinrichsen et al. 2013. PubMed ID: 23403630; Wanat et al. 2007. PubMed ID: 17210669; Ou et al. 2007. PubMed ID: 17594722; Drost et al. 2010. PubMed ID: 20020535). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89959/). This variant is interpreted as pathogenic.

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
Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing.	Alqahtani M	Familial cancer	2018	PMID: 28643016
Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm.	Morris B	BMC genetics	2016	PMID: 27363726
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis.	Hinrichsen I	Clinical cancer research : an official journal of the American Association for Cancer Research	2013	PMID: 23403630
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.	Hardt K	Familial cancer	2011	PMID: 21404117
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.	Kansikas M	Human mutation	2011	PMID: 21120944
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.	Kosinski J	Human mutation	2010	PMID: 20533529
A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1.	Drost M	Human mutation	2010	PMID: 20020535
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.	Takahashi M	Cancer research	2007	PMID: 17510385
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.	Raevaara TE	Gastroenterology	2005	PMID: 16083711
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1961C%3ET	-	-	-	-

Text-mined citations for rs63750726 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.1961C>T (p.Pro654Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750726 ...