NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 15, 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:: RCV000129313.8

Allele description [Variation Report for NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg)]

NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg)

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.1438G>C (p.Gly480Arg)

HGVS:

NC_000007.14:g.5987327C>G
NG_008466.1:g.26780G>C
NM_000535.7:c.1438G>CMANE SELECT
NM_001322003.2:c.1033G>C
NM_001322004.2:c.1033G>C
NM_001322005.2:c.1033G>C
NM_001322006.2:c.1282G>C
NM_001322007.2:c.1120G>C
NM_001322008.2:c.1120G>C
NM_001322009.2:c.1033G>C
NM_001322010.2:c.877G>C
NM_001322011.2:c.505G>C
NM_001322012.2:c.505G>C
NM_001322013.2:c.865G>C
NM_001322014.2:c.1438G>C
NM_001322015.2:c.1129G>C
NP_000526.2:p.Gly480Arg
NP_001308932.1:p.Gly345Arg
NP_001308933.1:p.Gly345Arg
NP_001308934.1:p.Gly345Arg
NP_001308935.1:p.Gly428Arg
NP_001308936.1:p.Gly374Arg
NP_001308937.1:p.Gly374Arg
NP_001308938.1:p.Gly345Arg
NP_001308939.1:p.Gly293Arg
NP_001308940.1:p.Gly169Arg
NP_001308941.1:p.Gly169Arg
NP_001308942.1:p.Gly289Arg
NP_001308943.1:p.Gly480Arg
NP_001308944.1:p.Gly377Arg
LRG_161t1:c.1438G>C
LRG_161:g.26780G>C
NC_000007.13:g.6026958C>G
NM_000535.5:c.1438G>C
NM_000535.6:c.1438G>C
NR_136154.1:n.1525G>C
p.H479Q

Protein change:

G169R

Links:

dbSNP: rs146848345

NCBI 1000 Genomes Browser:

rs146848345

Molecular consequence:

NM_000535.7:c.1438G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1282G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.877G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.505G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.505G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.865G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1438G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1129G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1525G>C - 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
SCV000184075	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000911857	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25318351, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184075

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 15, 2023)

germline

clinical testing

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

Citation Link,

SCV000911857

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 15, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Use of panel tests in place of single gene tests in the cancer genetics clinic.

Yorczyk A, Robinson LS, Ross TS.

Clin Genet. 2015 Sep;88(3):278-82. doi: 10.1111/cge.12488. Epub 2014 Oct 16.

PubMed [citation]

PMID:: 25318351

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, SCV000184075.4

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

Description

The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1438. The glycine at codon 480 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified once and classified as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). This amino acid position is not 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, SCV000911857.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glycine with arginine at codon 480 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 a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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: Nov 24, 2024

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