VCV000650237.27 - ClinVar

NM_000791.4(DHFR):c.-254G>A

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.

(8)

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_000791.4(DHFR):c.-254G>A

Variation ID: 650237 Accession: VCV000650237.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q14.1 5: 80654743 (GRCh38) [ NCBI UCSC ] 5: 79950562 (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	Aug 14, 2019	Sep 29, 2024	Sep 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000791.4:c.-254G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NM_002439.5:c.16C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002430.3:p.Pro6Ser	missense
NM_001290354.2:c.-360G>A		5 prime UTR
NM_001290357.2:c.-254G>A		5 prime UTR
NR_110936.2:n.241G>A		non-coding transcript variant
NC_000005.10:g.80654743C>T
NC_000005.9:g.79950562C>T
NG_016607.2:g.5269C>T
NG_023304.1:g.5239G>A
NG_105205.1:g.339C>T
NG_105205.2:g.366C>T

... more HGVS ... less HGVS

Protein change

P6S

Other names

Canonical SPDI

NC_000005.10:80654742: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 0.00013

Trans-Omics for Precision Medicine (TOPMed) 0.00014

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Exome Aggregation Consortium (ExAC) 0.00016

The Genome Aggregation Database (gnomAD) 0.00016

Links

dbSNP: rs374904719 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.
DHFR		-	-	GRCh38 GRCh37	111	660
MSH3		-	-	GRCh38 GRCh37	4009	4694

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 (3)	criteria provided, multiple submitters, no conflicts	Sep 5, 2024	RCV000805347.13
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 14, 2023	RCV001012792.7
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV001800890.7
MSH3-related disorder	Uncertain significance (1)	criteria provided, single submitter	Aug 17, 2023	RCV003413613.4
Endometrial carcinoma	Uncertain significance (1)	criteria provided, single submitter	Mar 28, 2024	RCV003467411.2

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 (Aug 21, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535976.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MSH3 c.16C>T (p.P6S) variant has not been reported in the literature to our knowledge. It was observed in 31/121172 chromosomes of the Non-Finnish European … (more) The MSH3 c.16C>T (p.P6S) variant has not been reported in the literature to our knowledge. It was observed in 31/121172 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 650237). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002570216.5 First in ClinVar: Sep 17, 2022 Last updated: Aug 18, 2023
Uncertain significance (Aug 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MSH3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115905.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MSH3 c.16C>T variant is predicted to result in the amino acid substitution p.Pro6Ser. To our knowledge, this variant has not been reported in the … (more) The MSH3 c.16C>T variant is predicted to result in the amino acid substitution p.Pro6Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-79950562-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Sep 19, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002046870.3 First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 29641532‚ 36652909 Comment: To the best of our knowledge, this variant has not been reported in individuals affected with an MSH3 related disease in the published literature. The … (more) To the best of our knowledge, this variant has not been reported in individuals affected with an MSH3 related disease in the published literature. The frequency of this variant in the general population, 0.00054 (14/25954 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000945300.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the MSH3 protein (p.Pro6Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the MSH3 protein (p.Pro6Ser). This variant is present in population databases (rs374904719, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 650237). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 (Mar 14, 2023)	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: SCV001173292.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29641532 Comment: The p.P6S variant (also known as c.16C>T), located in coding exon 1 of the MSH3 gene, results from a C to T substitution at nucleotide … (more) The p.P6S variant (also known as c.16C>T), located in coding exon 1 of the MSH3 gene, results from a C to T substitution at nucleotide position 16. The proline at codon 6 is replaced by serine, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197004.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Sep 05, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002571221.4 First in ClinVar: Sep 17, 2022 Last updated: Sep 29, 2024	Comment: In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; … (more) In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 36652909, 29641532) (less)

Comment:

The MSH3 c.16C>T variant is predicted to result in the amino acid substitution p.Pro6Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-79950562-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

To the best of our knowledge, this variant has not been reported in individuals affected with an MSH3 related disease in the published literature. The frequency of this variant in the general population, 0.00054 (14/25954 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the MSH3 protein (p.Pro6Ser). This variant is present in population databases (rs374904719, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 650237). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

The p.P6S variant (also known as c.16C>T), located in coding exon 1 of the MSH3 gene, results from a C to T substitution at nucleotide position 16. The proline at codon 6 is replaced by serine, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 36652909, 29641532)

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
Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.	Álvarez-Prado ÁF	Cell reports. Medicine	2023	PMID: 36652909
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.	Pritchard AL	PloS one	2018	PMID: 29641532

Text-mined citations for rs374904719 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000791.4(DHFR):c.-254G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs374904719 ...