NM_000535.7(PMS2):c.493A>G (p.Thr165Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 20, 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:: RCV000580103.7

Allele description [Variation Report for NM_000535.7(PMS2):c.493A>G (p.Thr165Ala)]

NM_000535.7(PMS2):c.493A>G (p.Thr165Ala)

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.493A>G (p.Thr165Ala)

HGVS:

NC_000007.14:g.6002497T>C
NG_008466.1:g.11610A>G
NM_000535.7:c.493A>GMANE SELECT
NM_001322003.2:c.88A>G
NM_001322004.2:c.88A>G
NM_001322005.2:c.88A>G
NM_001322006.2:c.493A>G
NM_001322007.2:c.175A>G
NM_001322008.2:c.175A>G
NM_001322009.2:c.88A>G
NM_001322010.2:c.88A>G
NM_001322011.2:c.-392A>G
NM_001322012.2:c.-392A>G
NM_001322013.2:c.88A>G
NM_001322014.2:c.493A>G
NM_001322015.2:c.184A>G
NP_000526.2:p.Thr165Ala
NP_001308932.1:p.Thr30Ala
NP_001308933.1:p.Thr30Ala
NP_001308934.1:p.Thr30Ala
NP_001308935.1:p.Thr165Ala
NP_001308936.1:p.Thr59Ala
NP_001308937.1:p.Thr59Ala
NP_001308938.1:p.Thr30Ala
NP_001308939.1:p.Thr30Ala
NP_001308942.1:p.Thr30Ala
NP_001308943.1:p.Thr165Ala
NP_001308944.1:p.Thr62Ala
LRG_161t1:c.493A>G
LRG_161:g.11610A>G
NC_000007.13:g.6042128T>C
NM_000535.5:c.493A>G
NM_000535.6:c.493A>G
NR_136154.1:n.580A>G

Protein change:

T165A

Links:

dbSNP: rs1554303902

NCBI 1000 Genomes Browser:

rs1554303902

Molecular consequence:

NM_001322011.2:c.-392A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-392A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.493A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.493A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.175A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.175A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.88A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.493A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.184A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.580A>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000686210	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002642711	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 11, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000686210

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 20, 2023)

germline

clinical testing

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

SCV002642711

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 11, 2019)

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, SCV000686210.4

#	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 threonine with alanine at codon 165 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, SCV002642711.2

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

Description

The p.T165A variant (also known as c.493A>G), located in coding exon 5 of the PMS2 gene, results from an A to G substitution at nucleotide position 493. The threonine at codon 165 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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: Sep 29, 2024

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