VCV000233391.14 - ClinVar

NM_000535.7(PMS2):c.2332T>A (p.Phe778Ile)

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_000535.7(PMS2):c.2332T>A (p.Phe778Ile)

Variation ID: 233391 Accession: VCV000233391.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5977701 (GRCh38) [ NCBI UCSC ] 7: 6017332 (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	Apr 29, 2017	May 1, 2024	Jun 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.2332T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Phe778Ile	missense
NM_001322003.2:c.1927T>A	NP_001308932.1:p.Phe643Ile	missense
NM_001322004.2:c.1927T>A	NP_001308933.1:p.Phe643Ile	missense
NM_001322005.2:c.1927T>A	NP_001308934.1:p.Phe643Ile	missense
NM_001322006.2:c.2176T>A	NP_001308935.1:p.Phe726Ile	missense
NM_001322007.2:c.2014T>A	NP_001308936.1:p.Phe672Ile	missense
NM_001322008.2:c.2014T>A	NP_001308937.1:p.Phe672Ile	missense
NM_001322009.2:c.1960T>A	NP_001308938.1:p.Phe654Ile	missense
NM_001322010.2:c.1771T>A	NP_001308939.1:p.Phe591Ile	missense
NM_001322011.2:c.1399T>A	NP_001308940.1:p.Phe467Ile	missense
NM_001322012.2:c.1399T>A	NP_001308941.1:p.Phe467Ile	missense
NM_001322013.2:c.1759T>A	NP_001308942.1:p.Phe587Ile	missense
NM_001322014.2:c.2365T>A	NP_001308943.1:p.Phe789Ile	missense
NM_001322015.2:c.2023T>A	NP_001308944.1:p.Phe675Ile	missense
NR_136154.1:n.2376T>A		non-coding transcript variant
NC_000007.14:g.5977701A>T
NC_000007.13:g.6017332A>T
NG_008466.1:g.36406T>A
LRG_161:g.36406T>A
LRG_161t1:c.2332T>A

... more HGVS ... less HGVS

Protein change

F778I, F591I, F643I, F672I, F675I, F587I, F726I, F467I, F654I, F789I

Other names

Canonical SPDI

NC_000007.14:5977700:A: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

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA10578647 dbSNP: rs876660374 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.
PMS2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5243	5345

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 (3)	criteria provided, multiple submitters, no conflicts	Jun 22, 2023	RCV000216483.8
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 19, 2017	RCV000486115.3
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Feb 8, 2023	RCV000697244.7
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 2, 2018	RCV000766549.1

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.
Uncertain significance (Aug 02, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567653.3 First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019	Comment: This variant is denoted PMS2 c.2332T>A at the cDNA level, p.Phe778Ile (F778I) at the protein level, and results in the change of a Phenylalanine to … (more) This variant is denoted PMS2 c.2332T>A at the cDNA level, p.Phe778Ile (F778I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of GENE are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Phe778Ile is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether PMS2 Phe778Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
Uncertain significance (Jul 19, 2017)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601842.2 First in ClinVar: Apr 29, 2017 Last updated: Jan 01, 2022
Uncertain significance (Jun 22, 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: SCV000277755.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Comment: The p.F778I variant (also known as c.2332T>A), located in coding exon 14 of the PMS2 gene, results from a T to A substitution at nucleotide … (more) The p.F778I variant (also known as c.2332T>A), located in coding exon 14 of the PMS2 gene, results from a T to A substitution at nucleotide position 2332. The phenylalanine at codon 778 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000822131.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Jan 14, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530291.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The PMS2 c.2332T>A (p.F778I) variant has been reported in 2 individuals with breast cancer but was also detected in 2 healthy individuals from a breast … (more) The PMS2 c.2332T>A (p.F778I) variant has been reported in 2 individuals with breast cancer but was also detected in 2 healthy individuals from a breast cancer case-control study (PMID: 33471991, 31159747). It was observed in 2/112866 chromosomes of the Non-Finnish European (NFE) subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 233391). In silico tools suggest the impact of the variant on protein function is deleterious, 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)	Publications: PubMed (2) PubMed: 33471991‚ 31159747
Uncertain significance (Feb 08, 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: SCV000825842.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 31159747 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 778 of the PMS2 protein (p.Phe778Ile). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 778 of the PMS2 protein (p.Phe778Ile). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with unspecified personal and/or family history of cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 233391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 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)

Comment:

This variant is denoted PMS2 c.2332T>A at the cDNA level, p.Phe778Ile (F778I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of GENE are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Phe778Ile is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether PMS2 Phe778Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.

Comment:

The p.F778I variant (also known as c.2332T>A), located in coding exon 14 of the PMS2 gene, results from a T to A substitution at nucleotide position 2332. The phenylalanine at codon 778 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 778 of the PMS2 protein (p.Phe778Ile). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with unspecified personal and/or family history of cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 233391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 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.

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
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747

Text-mined citations for rs876660374 ...

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_000535.7(PMS2):c.2332T>A (p.Phe778Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876660374 ...