VCV001779452.2 - ClinVar

NM_000249.4(MLH1):c.1754T>G (p.Leu585Arg)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.1754T>G (p.Leu585Arg)

Variation ID: 1779452 Accession: VCV001779452.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37047541 (GRCh38) [ NCBI UCSC ] 3: 37089032 (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	Nov 29, 2022	May 1, 2024	Mar 8, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1754T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Leu585Arg	missense
NM_001167617.3:c.1460T>G	NP_001161089.1:p.Leu487Arg	missense
NM_001167618.3:c.1031T>G	NP_001161090.1:p.Leu344Arg	missense
NM_001167619.3:c.1031T>G	NP_001161091.1:p.Leu344Arg	missense
NM_001258271.2:c.1754T>G	NP_001245200.1:p.Leu585Arg	missense
NM_001258273.2:c.1031T>G	NP_001245202.1:p.Leu344Arg	missense
NM_001258274.3:c.1031T>G	NP_001245203.1:p.Leu344Arg	missense
NM_001354615.2:c.1031T>G	NP_001341544.1:p.Leu344Arg	missense
NM_001354616.2:c.1031T>G	NP_001341545.1:p.Leu344Arg	missense
NM_001354617.2:c.1031T>G	NP_001341546.1:p.Leu344Arg	missense
NM_001354618.2:c.1031T>G	NP_001341547.1:p.Leu344Arg	missense
NM_001354619.2:c.1031T>G	NP_001341548.1:p.Leu344Arg	missense
NM_001354620.2:c.1460T>G	NP_001341549.1:p.Leu487Arg	missense
NM_001354621.2:c.731T>G	NP_001341550.1:p.Leu244Arg	missense
NM_001354622.2:c.731T>G	NP_001341551.1:p.Leu244Arg	missense
NM_001354623.2:c.731T>G	NP_001341552.1:p.Leu244Arg	missense
NM_001354624.2:c.680T>G	NP_001341553.1:p.Leu227Arg	missense
NM_001354625.2:c.680T>G	NP_001341554.1:p.Leu227Arg	missense
NM_001354626.2:c.680T>G	NP_001341555.1:p.Leu227Arg	missense
NM_001354627.2:c.680T>G	NP_001341556.1:p.Leu227Arg	missense
NM_001354628.2:c.1754T>G	NP_001341557.1:p.Leu585Arg	missense
NM_001354629.2:c.1655T>G	NP_001341558.1:p.Leu552Arg	missense
NM_001354630.2:c.1732-976T>G		intron variant
NC_000003.12:g.37047541T>G
NC_000003.11:g.37089032T>G
NG_007109.2:g.59192T>G
LRG_216:g.59192T>G
LRG_216t1:c.1754T>G	LRG_216p1:p.Leu585Arg
	P40692:p.Leu585Arg

... more HGVS ... less HGVS

Protein change

L585R, L227R, L344R, L552R, L244R, L487R

Other names

Canonical SPDI

NC_000003.12:37047540:T: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.

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

Links

dbSNP: rs267607865 UniProtKB: P40692#VAR_054534 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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 8, 2021	RCV002401601.2

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 08, 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: SCV002711673.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 12624141‚ 21642682‚ 24415873‚ 29967336 Comment: The p.L585R variant (also known as c.1754T>G), located in coding exon 16 of the MLH1 gene, results from a T to G substitution at nucleotide … (more) The p.L585R variant (also known as c.1754T>G), located in coding exon 16 of the MLH1 gene, results from a T to G substitution at nucleotide position 1754. The leucine at codon 585 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in French families suspected of having HNPCC/Lynch syndrome and in one family that met Amsterdam II criteria, segregation with disease was seen in three affected individuals (Küry S et al. World J Gastroenterol, 2014 Jan;20:204-13; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Furthermore, probands had Lynch syndrome associated tumors that demonstrated absent MLH1/PMS2 on immunohistochemistry and/or high microsatellite instability; however, a sibling of one of the probands, who also tested positive for this variant, had microsatellite stable endometrial cancer (Baert-Desurmont S et al. Eur J Hum Genet, 2018 11;26:1597-1602; Küry S et al. World J Gastroenterol, 2014 Jan;20:204-13). 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 conflicting at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The p.L585R variant (also known as c.1754T>G), located in coding exon 16 of the MLH1 gene, results from a T to G substitution at nucleotide position 1754. The leucine at codon 585 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in French families suspected of having HNPCC/Lynch syndrome and in one family that met Amsterdam II criteria, segregation with disease was seen in three affected individuals (Küry S et al. World J Gastroenterol, 2014 Jan;20:204-13; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Furthermore, probands had Lynch syndrome associated tumors that demonstrated absent MLH1/PMS2 on immunohistochemistry and/or high microsatellite instability; however, a sibling of one of the probands, who also tested positive for this variant, had microsatellite stable endometrial cancer (Baert-Desurmont S et al. Eur J Hum Genet, 2018 11;26:1597-1602; Küry S et al. World J Gastroenterol, 2014 Jan;20:204-13). 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 conflicting 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes.	Baert-Desurmont S	European journal of human genetics : EJHG	2018	PMID: 29967336
Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles.	Küry S	World journal of gastroenterology	2014	PMID: 24415873
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.	Bonadona V	JAMA	2011	PMID: 21642682
Cancer risk in 348 French MSH2 or MLH1 gene carriers.	Parc Y	Journal of medical genetics	2003	PMID: 12624141

Text-mined citations for rs267607865 ...

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 May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.1754T>G (p.Leu585Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267607865 ...