NM_000535.7(PMS2):c.88C>T (p.Gln30Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000131992.10

Allele description [Variation Report for NM_000535.7(PMS2):c.88C>T (p.Gln30Ter)]

NM_000535.7(PMS2):c.88C>T (p.Gln30Ter)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.88C>T (p.Gln30Ter)

HGVS:

NC_000007.14:g.6005967G>A
NG_008466.1:g.8140C>T
NG_050738.1:g.1717G>A
NM_000535.7:c.88C>TMANE SELECT
NM_001322003.2:c.-318C>T
NM_001322004.2:c.-242-1909C>T
NM_001322005.2:c.-318C>T
NM_001322006.2:c.88C>T
NM_001322007.2:c.-128C>T
NM_001322008.2:c.-52-1909C>T
NM_001322009.2:c.-318C>T
NM_001322010.2:c.-242-1909C>T
NM_001322011.2:c.-797C>T
NM_001322012.2:c.-797C>T
NM_001322013.2:c.-318C>T
NM_001322014.2:c.88C>T
NM_001322015.2:c.-397C>T
NP_000526.2:p.Gln30Ter
NP_001308935.1:p.Gln30Ter
NP_001308943.1:p.Gln30Ter
LRG_161t1:c.88C>T
LRG_161:g.8140C>T
NC_000007.13:g.6045598G>A
NM_000535.5:c.88C>T
NM_000535.6:c.88C>T
NR_136154.1:n.175C>T
p.Gln30X
p.Q30*

Protein change:

Q30*

Links:

dbSNP: rs141577476

NCBI 1000 Genomes Browser:

rs141577476

Molecular consequence:

NM_001322003.2:c.-318C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-318C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-128C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-318C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-797C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-797C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-318C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-397C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-242-1909C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1909C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1909C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_136154.1:n.175C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.88C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.88C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.88C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187050	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 18, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25856668, 32719484 Citation Link,
SCV000905476	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25856668, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187050

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 18, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000905476

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 5, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Grzymski JJ, Elhanan G, Morales Rosado JA, Smith E, Schlauch KA, Read R, Rowan C, Slotnick N, Dabe S, Metcalf WJ, Lipp B, Reed H, Sharma L, Levin E, Kao J, Rashkin M, Bowes J, Dunaway K, Slonim A, Washington N, Ferber M, Bolze A, et al.

Nat Med. 2020 Aug;26(8):1235-1239. doi: 10.1038/s41591-020-0982-5. Epub 2020 Jul 27.

PubMed [citation]

PMID:: 32719484

PMS2 monoallelic mutation carriers: the known unknown.

Goodenberger ML, Thomas BC, Riegert-Johnson D, Boland CR, Plon SE, Clendenning M, Win AK, Senter L, Lipkin SM, Stadler ZK, Macrae FA, Lynch HT, Weitzel JN, de la Chapelle A, Syngal S, Lynch P, Parry S, Jenkins MA, Gallinger S, Holter S, Aronson M, Newcomb PA, et al.

Genet Med. 2016 Jan;18(1):13-9. doi: 10.1038/gim.2015.27. Epub 2015 Apr 9. Review.

PubMed [citation]

PMID:: 25856668
PMCID:: PMC4834863

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000187050.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Q30* pathogenic mutation (also known as c.88C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 88. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration has been reported in an individual with endometrial and ovarian cancers with loss of PMS2 on immunohistochemistry (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9). This alteration was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000905476.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant changes 1 nucleotide in exon 2 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial and ovarian cancer whose tumor showed the loss of PMS2 via immunohistochemistry analysis (PMID: 25856668). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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

Last Updated: Jun 17, 2024

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