VCV000182534.11 - ClinVar

NM_000249.4(MLH1):c.19G>T (p.Val7Phe)

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.

(4)

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(3); Benign(1)

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.19G>T (p.Val7Phe)

Variation ID: 182534 Accession: VCV000182534.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 36993566 (GRCh38) [ NCBI UCSC ] 3: 37035057 (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	Feb 24, 2015	May 1, 2024	Nov 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.19G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Val7Phe	missense
NM_001167617.3:c.-498G>T		5 prime UTR
NM_001167618.3:c.-927G>T		5 prime UTR
NM_001167619.3:c.-840G>T		5 prime UTR
NM_001258271.2:c.19G>T	NP_001245200.1:p.Val7Phe	missense
NM_001258273.2:c.-614G>T		5 prime UTR
NM_001258274.3:c.-1077G>T		5 prime UTR
NM_001354615.2:c.-608G>T		5 prime UTR
NM_001354616.2:c.-608G>T		5 prime UTR
NM_001354617.2:c.-700G>T		5 prime UTR
NM_001354618.2:c.-932G>T		5 prime UTR
NM_001354619.2:c.-1056G>T		5 prime UTR
NM_001354620.2:c.-266G>T		5 prime UTR
NM_001354621.2:c.-1025G>T		5 prime UTR
NM_001354622.2:c.-1138G>T		5 prime UTR
NM_001354623.2:c.-1047G>T		5 prime UTR
NM_001354624.2:c.-808G>T		5 prime UTR
NM_001354625.2:c.-706G>T		5 prime UTR
NM_001354626.2:c.-803G>T		5 prime UTR
NM_001354627.2:c.-1035G>T		5 prime UTR
NM_001354628.2:c.19G>T	NP_001341557.1:p.Val7Phe	missense
NM_001354629.2:c.19G>T	NP_001341558.1:p.Val7Phe	missense
NM_001354630.2:c.19G>T	NP_001341559.1:p.Val7Phe	missense
NC_000003.12:g.36993566G>T
NC_000003.11:g.37035057G>T
NG_007109.2:g.5217G>T
NG_008418.1:g.4739C>A
LRG_216:g.5217G>T
LRG_216t1:c.19G>T	LRG_216p1:p.Val7Phe

... more HGVS ... less HGVS

Protein change

V7F

Other names

p.V7F:GTT>TTT

Canonical SPDI

NC_000003.12:36993565:G: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00011

Links

ClinGen: CA008120 dbSNP: rs730881746 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 provided	Uncertain significance (1)	criteria provided, single submitter	Feb 17, 2022	RCV000160549.3
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Nov 18, 2023	RCV000703809.5
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 19, 2021	RCV001804884.4

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 (May 03, 2021)	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: SCV002053390.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: This missense variant replaces valine with phenylalanine at codon 7 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces valine with phenylalanine at codon 7 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 an individual affected with Lynch syndrome (PMID: 27601186) or an individual suspected of having Lynch syndrome (PMID: 32973888). This variant has been identified in 33/282876 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)
Benign (Nov 18, 2023)	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: SCV000832728.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (May 19, 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: SCV002717783.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 27601186‚ 32973888 Comment: The p.V7F variant (also known as c.19G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide … (more) The p.V7F variant (also known as c.19G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 19. The valine at codon 7 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was observed in a 32 year old male with Lynch-like syndrome (LLS) in a cohort of 81 patients with LLS and 47 patients with Lynch syndrome who all had mismatch repair deficient colorectal cancer (Xu Y et al. Front Genet, 2020 Aug;11:991). In addition, this alteration was reported in one Sweedish family who meet criteria for clinical testing for Lynch syndrome (Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835). 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)
Uncertain significance (Feb 17, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211127.13 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a family with Lynch syndrome (Lagerstedt-Robinson 2016); This variant is … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a family with Lynch syndrome (Lagerstedt-Robinson 2016); This variant is associated with the following publications: (PMID: 27601186, 22753075) (less)

Comment:

This missense variant replaces valine with phenylalanine at codon 7 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 an individual affected with Lynch syndrome (PMID: 27601186) or an individual suspected of having Lynch syndrome (PMID: 32973888). This variant has been identified in 33/282876 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.V7F variant (also known as c.19G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 19. The valine at codon 7 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was observed in a 32 year old male with Lynch-like syndrome (LLS) in a cohort of 81 patients with LLS and 47 patients with Lynch syndrome who all had mismatch repair deficient colorectal cancer (Xu Y et al. Front Genet, 2020 Aug;11:991). In addition, this alteration was reported in one Sweedish family who meet criteria for clinical testing for Lynch syndrome (Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835). 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.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a family with Lynch syndrome (Lagerstedt-Robinson 2016); This variant is associated with the following publications: (PMID: 27601186, 22753075)

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
Comparison of Molecular, Clinicopathological, and Pedigree Differences Between Lynch-Like and Lynch Syndromes.	Xu Y	Frontiers in genetics	2020	PMID: 32973888
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.	Lagerstedt-Robinson K	Oncology reports	2016	PMID: 27601186

Text-mined citations for rs730881746 ...

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.19G>T (p.Val7Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730881746 ...