NM_000314.8(PTEN):c.882T>G (p.Ser294Arg) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 8, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000121909.19

Allele description [Variation Report for NM_000314.8(PTEN):c.882T>G (p.Ser294Arg)]

NM_000314.8(PTEN):c.882T>G (p.Ser294Arg)

Gene:

PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.8(PTEN):c.882T>G (p.Ser294Arg)

Other names:

p.S294R:AGT>AGG; NM_000314.6(PTEN):c.882T>G; NM_000314.8(PTEN):c.882T>G

HGVS:

NC_000010.11:g.87960974T>G
NG_007466.2:g.102536T>G
NM_000314.8:c.882T>GMANE SELECT
NM_001304717.5:c.1401T>G
NM_001304718.2:c.291T>G
NP_000305.3:p.Ser294Arg
NP_001291646.4:p.Ser467Arg
NP_001291647.1:p.Ser97Arg
LRG_311t1:c.882T>G
LRG_311:g.102536T>G
NC_000010.10:g.89720731T>G
NM_000314.4:c.882T>G
NM_000314.6:c.882T>G
NM_000314.7:c.882T>G
p.S294R

Protein change:

S294R

Links:

dbSNP: rs143335584

NCBI 1000 Genomes Browser:

rs143335584

Molecular consequence:

NM_000314.8:c.882T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1401T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.291T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000086113	ITMI	no classification provided	not provided	germline	reference population	PubMed (1) [See all records that cite this PMID]
SCV000696544	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 8, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24728327, 25186627, 28135145, 26580448, 26800850, 23161105, 38311546 Citation Link,
SCV002069034	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000086113

ITMI

no classification provided

not provided

germline

reference population

PubMed (1)
[See all records that cite this PMID]

SCV000696544

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 8, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV002069034

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 16, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
African	germline	unknown	not provided	not provided	not provided	43	not provided	reference population
African_European	germline	unknown	not provided	not provided	not provided	46	not provided	reference population
Central_Asian	germline	unknown	not provided	not provided	not provided	50	not provided	reference population
East_Asian	germline	unknown	not provided	not provided	not provided	62	not provided	reference population
European	germline	unknown	not provided	not provided	not provided	331	not provided	reference population
Hispanic	germline	unknown	not provided	not provided	not provided	118	not provided	reference population
Whole_cohort	germline	unknown	not provided	not provided	not provided	681	not provided	reference population

Citations

PubMed

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

See all PubMed Citations (8)

Details of each submission

From ITMI, SCV000086113.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African	not provided	not provided	not provided	reference population	PubMed (1)
2	African_European	not provided	not provided	not provided	reference population	PubMed (1)
3	Central_Asian	not provided	not provided	not provided	reference population	PubMed (1)
4	East_Asian	not provided	not provided	not provided	reference population	PubMed (1)
5	European	not provided	not provided	not provided	reference population	PubMed (1)
6	Hispanic	not provided	not provided	not provided	reference population	PubMed (1)
7	Whole_cohort	not provided	not provided	not provided	reference population	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	43	not provided	discovery		not provided	0	not provided	not provided
2	germline	unknown	46	not provided	discovery		not provided	0	not provided	not provided
3	germline	unknown	50	not provided	discovery		not provided	0	not provided	not provided
4	germline	unknown	62	not provided	discovery		not provided	0	not provided	not provided
5	germline	unknown	331	not provided	discovery		not provided	0	not provided	not provided
6	germline	unknown	118	not provided	discovery		not provided	0.0042	not provided	not provided
7	germline	unknown	681	not provided	discovery		not provided	0.0007	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696544.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: PTEN c.882T>G (p.Ser294Arg) results in a non-conservative amino acid change located in the Tensin phosphatase, C2 domain (IPR014020) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 1614844 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (1.6e-05). c.882T>G has been reported in the literature in individuals affected with various types of cancers including but not limited to neuroblastoma, colorectal cancer and prostate cancer (example: Zhang_2015, Yurgelun_2017, Coelho_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 25186627, 28135145, 26580448, 26800850, 23161105, 38311546). ClinVar contains an entry for this variant (Variation ID: 127693). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002069034.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the PTEN gene demonstrated a sequence change, c.882T>G, in exon 8 that results in an amino acid change, p.Ser294Arg. This sequence change has been described in the gnomAD database with a frequency of 0.052% in the African American/African subpopulation (dbSNP rs143335584). The p.Ser294Arg change affects a moderately conserved amino acid residue located in a domain of the PTEN protein that is known to be functional. The p.Ser294Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with colorectal cancer who underwent germline genetic testing and it was considered a variant of unknown significance (PMID: 28135145). Due insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser294Arg change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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