NM_000535.7(PMS2):c.2069A>G (p.Lys690Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 10, 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:: RCV001014304.5

Allele description [Variation Report for NM_000535.7(PMS2):c.2069A>G (p.Lys690Arg)]

NM_000535.7(PMS2):c.2069A>G (p.Lys690Arg)

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.2069A>G (p.Lys690Arg)

HGVS:

NC_000007.14:g.5982929T>C
NG_008466.1:g.31178A>G
NM_000535.7:c.2069A>GMANE SELECT
NM_001322003.2:c.1664A>G
NM_001322004.2:c.1664A>G
NM_001322005.2:c.1664A>G
NM_001322006.2:c.1913A>G
NM_001322007.2:c.1751A>G
NM_001322008.2:c.1751A>G
NM_001322009.2:c.1664A>G
NM_001322010.2:c.1508A>G
NM_001322011.2:c.1136A>G
NM_001322012.2:c.1136A>G
NM_001322013.2:c.1496A>G
NM_001322014.2:c.2069A>G
NM_001322015.2:c.1760A>G
NP_000526.2:p.Lys690Arg
NP_001308932.1:p.Lys555Arg
NP_001308933.1:p.Lys555Arg
NP_001308934.1:p.Lys555Arg
NP_001308935.1:p.Lys638Arg
NP_001308936.1:p.Lys584Arg
NP_001308937.1:p.Lys584Arg
NP_001308938.1:p.Lys555Arg
NP_001308939.1:p.Lys503Arg
NP_001308940.1:p.Lys379Arg
NP_001308941.1:p.Lys379Arg
NP_001308942.1:p.Lys499Arg
NP_001308943.1:p.Lys690Arg
NP_001308944.1:p.Lys587Arg
LRG_161t1:c.2069A>G
LRG_161:g.31178A>G
NC_000007.13:g.6022560T>C
NM_000535.5:c.2069A>G
NR_136154.1:n.2156A>G

Protein change:

K379R

Links:

dbSNP: rs876661164

NCBI 1000 Genomes Browser:

rs876661164

Molecular consequence:

NM_000535.7:c.2069A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1664A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1664A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1664A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1913A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1664A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1508A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1496A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2069A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1760A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2156A>G - 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

Recent activity

Clear Turn Off Turn On

Homo sapiens regulator of telomere elongation helicase 1 (RTEL1), transcript var...
Homo sapiens regulator of telomere elongation helicase 1 (RTEL1), transcript variant 4, mRNA
gi|545688901|ref|NM_001283010.1|

Nucleotide
INPP5E [Macaca fascicularis]
INPP5E [Macaca fascicularis]
Gene ID:102140416

Gene
CYP4F2 cytochrome P450 family 4 subfamily F member 2 [Macaca fascicularis]
CYP4F2 cytochrome P450 family 4 subfamily F member 2 [Macaca fascicularis]
Gene ID:102134301

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001174998	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 10, 2024)	germline	clinical testing	Citation Link,
SCV004359562	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 16, 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

SCV001174998

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 10, 2024)

germline

clinical testing

Citation Link,

SCV004359562

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 16, 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

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, SCV001174998.5

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

Description

The p.K690R variant (also known as c.2069A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2069. The lysine at codon 690 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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, SCV004359562.1

#	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 lysine with arginine at codon 690 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 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.

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine