VCV000090251.18 - ClinVar

NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)

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.

(6)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)

Variation ID: 90251 Accession: VCV000090251.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37008866 (GRCh38) [ NCBI UCSC ] 3: 37050357 (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	Jun 17, 2024	Mar 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.506C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Pro169Leu	missense
NM_001167617.3:c.212C>T	NP_001161089.1:p.Pro71Leu	missense
NM_001167618.3:c.-218C>T		5 prime UTR
NM_001167619.3:c.-179+1803C>T		intron variant
NM_001258271.2:c.506C>T	NP_001245200.1:p.Pro169Leu	missense
NM_001258273.2:c.-218C>T		5 prime UTR
NM_001258274.3:c.-218C>T		5 prime UTR
NM_001354615.2:c.-179+1803C>T		intron variant
NM_001354616.2:c.-179+1803C>T		intron variant
NM_001354617.2:c.-218C>T		5 prime UTR
NM_001354618.2:c.-218C>T		5 prime UTR
NM_001354619.2:c.-218C>T		5 prime UTR
NM_001354620.2:c.212C>T	NP_001341549.1:p.Pro71Leu	missense
NM_001354621.2:c.-311C>T		5 prime UTR
NM_001354622.2:c.-424C>T		5 prime UTR
NM_001354623.2:c.-424C>T		5 prime UTR
NM_001354624.2:c.-321C>T		5 prime UTR
NM_001354625.2:c.-282+1803C>T		intron variant
NM_001354626.2:c.-321C>T		5 prime UTR
NM_001354627.2:c.-321C>T		5 prime UTR
NM_001354628.2:c.506C>T	NP_001341557.1:p.Pro169Leu	missense
NM_001354629.2:c.407C>T	NP_001341558.1:p.Pro136Leu	missense
NM_001354630.2:c.506C>T	NP_001341559.1:p.Pro169Leu	missense
NC_000003.12:g.37008866C>T
NC_000003.11:g.37050357C>T
NG_007109.2:g.20517C>T
LRG_216:g.20517C>T
LRG_216t1:c.506C>T	LRG_216p1:p.Pro169Leu

... more HGVS ... less HGVS

Protein change

P169L, P136L, P71L

Other names

Canonical SPDI

NC_000003.12:37008865: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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA010747 dbSNP: rs63750834 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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2023	RCV000218502.9
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2024	RCV000524304.8
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 21, 2023	RCV003441740.1
Colorectal cancer, hereditary nonpolyposis, type 2	Uncertain significance (1)	criteria provided, single submitter	Mar 5, 2024	RCV004566930.1
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 23, 2023	RCV003997132.2

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 (Mar 05, 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: SCV005057966.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Jan 18, 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: SCV001342529.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 16237216 Comment: This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and in a suspected hereditary nonpolyposis colorectal cancer family (Salehi, 2008). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 30, 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: SCV000543524.8 First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28492532‚ 31391288‚ 26333163 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the MLH1 protein (p.Pro169Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the MLH1 protein (p.Pro169Leu). This variant is present in population databases (rs63750834, gnomAD 0.0009%). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 90251). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). Studies have shown this missense change is associated with skipping of exon 6, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004167716.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in a patient with mixed proximal gastric cancer with deficient MLH1 by IHC, who also harbored a pathogenic MLH1 variant (PMID: 16237216); This variant is associated with the following publications: (PMID: 26333163, 32027066, 33471991, 22753075, 16237216) (less)
Uncertain Significance (Oct 23, 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: SCV004835294.1 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 (1) PubMed: 16237216 Comment: This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and a suspected hereditary nonpolyposis colorectal cancer family (https://jsciences.ut.ac.ir/article_31909.html). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 4
Uncertain significance (Mar 15, 2022)	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: SCV000277501.7 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 16237216‚ 26333163 Comment: The p.P169L variant (also known as c.506C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide … (more) The p.P169L variant (also known as c.506C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 506. The proline at codon 169 is replaced by leucine, an amino acid with similar properties. This alteration was identified in a cohort of Iranian patients whose personal and family cancer history meets the Amsterdam criteria (Salehi M et al. J Sci I Iran. 2009; 20(1):7-12). This variant was reportedly detected in conjunction (phase unknown) with a pathogenic mutation in MLH1 in a 35-year-old male with mixed proximal gastric cancer (Bacani J et al. J Mol Diagn. 2005 Oct;7:465-77). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and in a suspected hereditary nonpolyposis colorectal cancer family (Salehi, 2008). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the MLH1 protein (p.Pro169Leu). This variant is present in population databases (rs63750834, gnomAD 0.0009%). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 90251). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). Studies have shown this missense change is associated with skipping of exon 6, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in a patient with mixed proximal gastric cancer with deficient MLH1 by IHC, who also harbored a pathogenic MLH1 variant (PMID: 16237216); This variant is associated with the following publications: (PMID: 26333163, 32027066, 33471991, 22753075, 16237216)

Comment:

This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and a suspected hereditary nonpolyposis colorectal cancer family (https://jsciences.ut.ac.ir/article_31909.html). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The p.P169L variant (also known as c.506C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 506. The proline at codon 169 is replaced by leucine, an amino acid with similar properties. This alteration was identified in a cohort of Iranian patients whose personal and family cancer history meets the Amsterdam criteria (Salehi M et al. J Sci I Iran. 2009; 20(1):7-12). This variant was reportedly detected in conjunction (phase unknown) with a pathogenic mutation in MLH1 in a 35-year-old male with mixed proximal gastric cancer (Bacani J et al. J Mol Diagn. 2005 Oct;7:465-77). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and a suspected hereditary nonpolyposis colorectal cancer family (https://jsciences.ut.ac.ir/article_31909.html). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.	Li S	Journal of medical genetics	2020	PMID: 31391288
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.	Niroula A	Human mutation	2015	PMID: 26333163
Tumor microsatellite instability in early onset gastric cancer.	Bacani J	The Journal of molecular diagnostics : JMD	2005	PMID: 16237216

Text-mined citations for rs63750834 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750834 ...