VCV000525783.16 - ClinVar

NM_000535.7(PMS2):c.929A>G (p.Tyr310Cys)

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.

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.929A>G (p.Tyr310Cys)

Variation ID: 525783 Accession: VCV000525783.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5992032 (GRCh38) [ NCBI UCSC ] 7: 6031663 (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	May 28, 2018	May 1, 2024	Nov 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.929A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Tyr310Cys	missense
NM_001322003.2:c.524A>G	NP_001308932.1:p.Tyr175Cys	missense
NM_001322004.2:c.524A>G	NP_001308933.1:p.Tyr175Cys	missense
NM_001322005.2:c.524A>G	NP_001308934.1:p.Tyr175Cys	missense
NM_001322006.2:c.929A>G	NP_001308935.1:p.Tyr310Cys	missense
NM_001322007.2:c.611A>G	NP_001308936.1:p.Tyr204Cys	missense
NM_001322008.2:c.611A>G	NP_001308937.1:p.Tyr204Cys	missense
NM_001322009.2:c.524A>G	NP_001308938.1:p.Tyr175Cys	missense
NM_001322010.2:c.524A>G	NP_001308939.1:p.Tyr175Cys	missense
NM_001322011.2:c.-5A>G		5 prime UTR
NM_001322012.2:c.-5A>G		5 prime UTR
NM_001322013.2:c.356A>G	NP_001308942.1:p.Tyr119Cys	missense
NM_001322014.2:c.929A>G	NP_001308943.1:p.Tyr310Cys	missense
NM_001322015.2:c.620A>G	NP_001308944.1:p.Tyr207Cys	missense
NR_136154.1:n.1016A>G		non-coding transcript variant
NC_000007.14:g.5992032T>C
NC_000007.13:g.6031663T>C
NG_008466.1:g.22075A>G
LRG_161:g.22075A>G
LRG_161t1:c.929A>G

... more HGVS ... less HGVS

Protein change

Y310C, Y207C, Y119C, Y175C, Y204C

Other names

Canonical SPDI

NC_000007.14:5992031:T:C

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) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA052522 dbSNP: rs372172981 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	5241	5343

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 nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Jan 14, 2019	RCV000630078.9
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 15, 2022	RCV001019128.3
Lynch syndrome 4 Mismatch repair cancer syndrome 4	Uncertain significance (1)	criteria provided, single submitter	Sep 23, 2021	RCV002507058.1
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 20, 2023	RCV004002790.2

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 (Jan 14, 2019)	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: SCV000751034.7 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Comment: 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 … (more) 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related disease. This variant is present in population databases (rs372172981, ExAC 0.01%). This sequence change replaces tyrosine with cysteine at codon 310 of the PMS2 protein (p.Tyr310Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. (less)
Uncertain significance (Jul 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: SCV001180450.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.Y310C variant (also known as c.929A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide … (more) The p.Y310C variant (also known as c.929A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide position 929. The tyrosine at codon 310 is replaced by cysteine, an amino acid with highly dissimilar properties. 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 (Sep 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Mismatch repair cancer syndrome 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002816859.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain Significance (Nov 20, 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: SCV004838199.1 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)	Comment: This missense variant replaces tyrosine with cysteine at codon 310 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces tyrosine with cysteine at codon 310 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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: 1

Comment:

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related disease. This variant is present in population databases (rs372172981, ExAC 0.01%). This sequence change replaces tyrosine with cysteine at codon 310 of the PMS2 protein (p.Tyr310Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine.

Comment:

The p.Y310C variant (also known as c.929A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide position 929. The tyrosine at codon 310 is replaced by cysteine, an amino acid with highly dissimilar properties. 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:

This missense variant replaces tyrosine with cysteine at codon 310 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs372172981 ...

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.929A>G (p.Tyr310Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs372172981 ...