NM_000535.7(PMS2):c.1748A>T (p.Glu583Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 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:: RCV000776738.5

Allele description [Variation Report for NM_000535.7(PMS2):c.1748A>T (p.Glu583Val)]

NM_000535.7(PMS2):c.1748A>T (p.Glu583Val)

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.1748A>T (p.Glu583Val)

HGVS:

NC_000007.14:g.5987017T>A
NG_008466.1:g.27090A>T
NM_000535.7:c.1748A>TMANE SELECT
NM_001322003.2:c.1343A>T
NM_001322004.2:c.1343A>T
NM_001322005.2:c.1343A>T
NM_001322006.2:c.1592A>T
NM_001322007.2:c.1430A>T
NM_001322008.2:c.1430A>T
NM_001322009.2:c.1343A>T
NM_001322010.2:c.1187A>T
NM_001322011.2:c.815A>T
NM_001322012.2:c.815A>T
NM_001322013.2:c.1175A>T
NM_001322014.2:c.1748A>T
NM_001322015.2:c.1439A>T
NP_000526.2:p.Glu583Val
NP_001308932.1:p.Glu448Val
NP_001308933.1:p.Glu448Val
NP_001308934.1:p.Glu448Val
NP_001308935.1:p.Glu531Val
NP_001308936.1:p.Glu477Val
NP_001308937.1:p.Glu477Val
NP_001308938.1:p.Glu448Val
NP_001308939.1:p.Glu396Val
NP_001308940.1:p.Glu272Val
NP_001308941.1:p.Glu272Val
NP_001308942.1:p.Glu392Val
NP_001308943.1:p.Glu583Val
NP_001308944.1:p.Glu480Val
LRG_161t1:c.1748A>T
LRG_161:g.27090A>T
NC_000007.13:g.6026648T>A
NM_000535.5:c.1748A>T
NM_000535.6:c.1748A>T
NR_136154.1:n.1835A>T

Protein change:

E272V

Links:

dbSNP: rs1562627848

NCBI 1000 Genomes Browser:

rs1562627848

Molecular consequence:

NM_000535.7:c.1748A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1343A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1343A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1343A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1592A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1430A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1430A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1343A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.815A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.815A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1175A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1748A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1439A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1835A>T - 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
SCV000912379	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004054918	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jul 30, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000912379

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 5, 2023)

germline

clinical testing

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

SCV004054918

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jul 30, 2023)

germline

clinical testing

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

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 Color Diagnostics, LLC DBA Color Health, SCV000912379.3

#	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 glutamic acid with valine at codon 583 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

From Ambry Genetics, SCV004054918.1

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

Description

The p.E583V variant (also known as c.1748A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1748. The glutamic acid at codon 583 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is conserved. 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

Last Updated: Feb 20, 2024

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