NM_000535.7(PMS2):c.88C>A (p.Gln30Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 24, 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:: RCV001018478.6

Allele description [Variation Report for NM_000535.7(PMS2):c.88C>A (p.Gln30Lys)]

NM_000535.7(PMS2):c.88C>A (p.Gln30Lys)

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>A (p.Gln30Lys)

HGVS:

NC_000007.14:g.6005967G>T
NG_008466.1:g.8140C>A
NG_050738.1:g.1717G>T
NM_000535.7:c.88C>AMANE SELECT
NM_001322003.2:c.-318C>A
NM_001322004.2:c.-242-1909C>A
NM_001322005.2:c.-318C>A
NM_001322006.2:c.88C>A
NM_001322007.2:c.-128C>A
NM_001322008.2:c.-52-1909C>A
NM_001322009.2:c.-318C>A
NM_001322010.2:c.-242-1909C>A
NM_001322011.2:c.-797C>A
NM_001322012.2:c.-797C>A
NM_001322013.2:c.-318C>A
NM_001322014.2:c.88C>A
NM_001322015.2:c.-397C>A
NP_000526.2:p.Gln30Lys
NP_001308935.1:p.Gln30Lys
NP_001308943.1:p.Gln30Lys
LRG_161t1:c.88C>A
LRG_161:g.8140C>A
NC_000007.13:g.6045598G>T
NM_000535.5:c.88C>A
NM_000535.6:c.88C>A
NR_136154.1:n.175C>A

Protein change:

Q30K

Links:

dbSNP: rs141577476

NCBI 1000 Genomes Browser:

rs141577476

Molecular consequence:

NM_001322003.2:c.-318C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-318C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-128C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-318C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-797C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-797C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-318C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-397C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-242-1909C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1909C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1909C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.88C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.88C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.88C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.175C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001179723	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002053226	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 31, 2023)	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

SCV001179723

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 24, 2023)

germline

clinical testing

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

Citation Link,

SCV002053226

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 31, 2023)

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

Citations

PubMed

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV001179723.4

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

Description

The p.Q30K variant (also known as c.88C>A), located in coding exon 2 of the PMS2 gene, results from a C to A substitution at nucleotide position 88. The glutamine at codon 30 is replaced by lysine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (ALL) (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.

#	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, SCV002053226.2

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

Description

This missense variant replaces glutamine with lysine at codon 30 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 been identified in 3/245770 chromosomes 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.

#	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: Oct 13, 2024

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