NM_000535.7(PMS2):c.632G>A (p.Arg211Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 30, 2024
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:: RCV000130297.18

Allele description [Variation Report for NM_000535.7(PMS2):c.632G>A (p.Arg211Gln)]

NM_000535.7(PMS2):c.632G>A (p.Arg211Gln)

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.632G>A (p.Arg211Gln)

Other names:

p.R211Q:CGA>CAA

HGVS:

NC_000007.14:g.5999181C>T
NG_008466.1:g.14926G>A
NM_000535.7:c.632G>AMANE SELECT
NM_001322003.2:c.227G>A
NM_001322004.2:c.227G>A
NM_001322005.2:c.227G>A
NM_001322006.2:c.632G>A
NM_001322007.2:c.314G>A
NM_001322008.2:c.314G>A
NM_001322009.2:c.227G>A
NM_001322010.2:c.227G>A
NM_001322011.2:c.-302G>A
NM_001322012.2:c.-302G>A
NM_001322013.2:c.133-1758G>A
NM_001322014.2:c.632G>A
NM_001322015.2:c.323G>A
NP_000526.2:p.Arg211Gln
NP_001308932.1:p.Arg76Gln
NP_001308933.1:p.Arg76Gln
NP_001308934.1:p.Arg76Gln
NP_001308935.1:p.Arg211Gln
NP_001308936.1:p.Arg105Gln
NP_001308937.1:p.Arg105Gln
NP_001308938.1:p.Arg76Gln
NP_001308939.1:p.Arg76Gln
NP_001308943.1:p.Arg211Gln
NP_001308944.1:p.Arg108Gln
LRG_161t1:c.632G>A
LRG_161:g.14926G>A
NC_000007.13:g.6038812C>T
NM_000535.5:c.632G>A
NM_000535.6:c.632G>A
NR_136154.1:n.719G>A
p.R211Q

Protein change:

R105Q

Links:

dbSNP: rs587781934

NCBI 1000 Genomes Browser:

rs587781934

Molecular consequence:

NM_001322011.2:c.-302G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-302G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.133-1758G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.323G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.719G>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
SCV000185146	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27616075, 31433215, 31992580, 32885271 Citation Link,
SCV000686223	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 28, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 27616075, 31433215, 31992580, 32628757, 32885271, 33471991, 34359559, 25741868
SCV002530372	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 9, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 27616075, 31433215, 31992580, 32628757, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185146

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 30, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000686223

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 28, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002530372

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 9, 2021)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

Lerner-Ellis J, Mighton C, Lazaro C, Watkins N, Di Gioacchino V, Wong A, Chang MC, Charames GS.

J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. doi: 10.1007/s00432-020-03377-6. Epub 2020 Sep 3. Erratum in: J Cancer Res Clin Oncol. 2021 Aug;147(8):2487. doi: 10.1007/s00432-020-03399-0.

PubMed [citation]

PMID:: 32885271

TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing.

Lesueur F, Eon-Marchais S, Bonnet-Boissinot S, Beauvallet J, Dondon MG, Golmard L, Rouleau E, Garrec C, Martinez M, Toulas C, Nguyen TD, Brayotel F, Crivelli L, Maugard CM, Bubien V, Sevenet N, Gesta P, Chieze-Valero S, Nambot S, Goussot V, Mari V, Popovici C, et al.

Cancers (Basel). 2021 Jul 21;13(15). doi:pii: 3659. 10.3390/cancers13153659.

PubMed [citation]

PMID:: 34359559
PMCID:: PMC8345200

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000185146.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R211Q variant (also known as c.632G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 632. The arginine at codon 211 is replaced by glutamine, an amino acid with highly similar properties. This alteration was seen in a patient diagnosed with ovarian cancer at age 72 (Kraus C. et al. Int. J. Cancer. 2017 Jan;140(1):95-102). This alteration was also seen in two patients diagnosed with colon cancer from Denmark and/or Sweden (Okkels H et al. Genet Test Mol Biomarkers, 2019 Sep;23:688-695). Additionally, this alteration was identified in an individual diagnosed with small bowel cancer at 51. (Wang Q et al. J Med Genet, 2020 07;57:487-499).This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant 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, SCV000686223.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces arginine with glutamine at codon 211 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and ovarian cancer (PMID: 27616075, 31433215, 31992580, 32628757). This variant has also been reported in individuals affected with breast cancer (PMID: 32885271, 33471991, 34359559), as well as ten healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 12/282866 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

From Sema4, Sema4, SCV002530372.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	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 20, 2024

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