NM_000535.7(PMS2):c.1419G>C (p.Glu473Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001889633.6

Allele description [Variation Report for NM_000535.7(PMS2):c.1419G>C (p.Glu473Asp)]

NM_000535.7(PMS2):c.1419G>C (p.Glu473Asp)

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.1419G>C (p.Glu473Asp)

HGVS:

NC_000007.14:g.5987346C>G
NG_008466.1:g.26761G>C
NM_000535.7:c.1419G>CMANE SELECT
NM_001322003.2:c.1014G>C
NM_001322004.2:c.1014G>C
NM_001322005.2:c.1014G>C
NM_001322006.2:c.1263G>C
NM_001322007.2:c.1101G>C
NM_001322008.2:c.1101G>C
NM_001322009.2:c.1014G>C
NM_001322010.2:c.858G>C
NM_001322011.2:c.486G>C
NM_001322012.2:c.486G>C
NM_001322013.2:c.846G>C
NM_001322014.2:c.1419G>C
NM_001322015.2:c.1110G>C
NP_000526.2:p.Glu473Asp
NP_001308932.1:p.Glu338Asp
NP_001308933.1:p.Glu338Asp
NP_001308934.1:p.Glu338Asp
NP_001308935.1:p.Glu421Asp
NP_001308936.1:p.Glu367Asp
NP_001308937.1:p.Glu367Asp
NP_001308938.1:p.Glu338Asp
NP_001308939.1:p.Glu286Asp
NP_001308940.1:p.Glu162Asp
NP_001308941.1:p.Glu162Asp
NP_001308942.1:p.Glu282Asp
NP_001308943.1:p.Glu473Asp
NP_001308944.1:p.Glu370Asp
LRG_161:g.26761G>C
NC_000007.13:g.6026977C>G
NR_136154.1:n.1506G>C

Protein change:

E162D

Links:

dbSNP: rs2128731146

NCBI 1000 Genomes Browser:

rs2128731146

Molecular consequence:

NM_000535.7:c.1419G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1014G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1014G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1014G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1263G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1101G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1101G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1014G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.858G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.486G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.486G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.846G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1419G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1110G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1506G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002163489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 28, 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

SCV002163489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 28, 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002163489.3

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 473 of the PMS2 protein (p.Glu473Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1390803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

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